bismuth- and iron-catalyzed three-component synthesis of ... · bismuth- and iron-catalyzed...
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SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2017, 49, 849–879paper
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Bismuth- and Iron-Catalyzed Three-Component Synthesis of α-Amino Acid Derivatives: A Simple and Convenient Route to α-ArylglycinesJuliette Halli‡ Angelika E. Schneider‡ Tamara Beisel Philipp Kramer Andrej Shemet Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology, Goethe-University Frankfurt, Max-von-Laue-Straße 7, 60439 Frankfurt am Main, [email protected]
‡ These authors contributed equally to this study.
H CO2R'
O+
Bi3+ or Fe3+
catalysis
(Het)Ar
CO2R'(Het)Ar-H
R
O
NH2
+
arylglycines64 examples8–95% yield
R
O
NH
R = aryl, alkyl, alkoxyR' = Et, i-Pr, H
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Received: 07.06.2016Accepted: 13.06.2016Published online: 29.07.2016DOI: 10.1055/s-0035-1561499; Art ID: ss-2016-z0412-op
Abstract Efficient bismuth- and iron-catalyzed three-component syn-theses of α-arylglycines have been developed. These methods provide ageneral, atom-economic route to various N-protected α-arylglycinesstarting from readily available amides (or carbamates), glyoxalates, and(hetero)arenes with water as the only by-product. Scope and limita-tions of bismuth- and iron-catalyzed reactions are discussed and com-pared. In addition, mechanistic investigations as well as initial foraysinto stereoselective three-component reactions are presented.
Key words multicomponent reactions, iron, bismuth, aza-Friedel–Crafts reaction, amino acids, homogeneous catalysis
α-Amino acids are of fundamental importance for biolo-gy, biochemistry, and chemistry.1,2 They form the backboneof proteins, an essential part of every living organism, andare used as common feedstock for the production of biode-gradable plastics, fertilizers, nutritional supplements, ordrugs.1,2 Many proteinogenic and nonproteinogenic α-ami-no acids have important biological, nonprotein-relatedfunctions, such as glutamate,1 an important neurotransmit-ter or glycine,3 the starting material for the biosynthesis ofporphyrin-type cofactors. With the expansion of the genet-ic code and the discovery of protein-based drugs, nonpro-teinogenic (or unnatural) α-amino acids have gained in-creasing attention.1,2 Among these nonproteinogenic α-amino acids, α-arylglycines are of particular importance, asthey are building blocks for various drugs, such as cardio-vascular agents4 and β-lactam antibiotics5 like amoxicillinand norcardicin A (Figure 1). The α-arylglycine moiety isalso part of numerous natural products, such as vancomy-cin6 or chloropeptin I7 (Figure 1). Expanding the organic
chemist’s tool box with novel efficient, modular and practi-cal methods for the synthesis of the α-arylglycine structureis therefore of great interest.8,9 Common procedures for thepreparation of these compounds are based on the additionof a nucleophile to an imine species, such as the Mannichreaction,10 the Strecker reaction,11 the Petasis–(Borono–Mannich) reaction,12 or aza-Friedel–Crafts-type reactions13
(Scheme 1).
Figure 1 α-Arylglycine moiety in biologically active substances
OH
N
CO2HH
HN
O
NOH
O
NH2HO2C H
H
Norcardicin A
N
S
O
MeMe
HO2C
HNH O
NH2
HO
Amoxicillin
Chloropeptin I
HO2CHN
O
N
Me
OHN
O
ClCl
OH
NH
OH
OHN
Cl Cl
OH
O
NH
O
O
Cl Cl
OHOH
HN
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Scheme 1 Different synthetic routes to α-arylglycines
However, these methods have some decisive drawbacks.Cyanides used in the Strecker reaction are highly toxic andthe subsequent hydrolysis of the nitrile function underacidic conditions curtails the functional group tolerance(Scheme 1, path A). The Petasis–(Borono–Mannich) reac-tion and related processes require prefunctionalized and of-ten expensive boronic acid derivatives (Scheme 1, path B).Another important approach is the direct amino- and ami-doalkylation of unfunctionalized (hetero)arenes (Scheme 1,path C).13,14 These aza-Friedel–Crafts-type reactions arebased on nucleophilic addition of arenes to highly electro-philic imines and especially N-acylimines. In combinationwith the in situ formation of the reactive N-acylimine spe-cies via condensation of an aldehyde and an amide, thesemethods enable the preparation of α-arylglycines with wa-ter as only by-product and offer a promising opportunityfor the sustainable and atom-economic synthesis of thisimportant compound class.15 However, reported aza-Friedel–Crafts-type reactions are often limited to very reac-tive (hetero)arenes or require stoichiometric amounts ofstrong Brønsted or Lewis acids.14 These restrictions lead toa rather small substrate scope and the formation of consid-erable amounts of waste and by-products.
In the course of our research on imine-based multicom-ponent reactions,16 we were able to develop three-compo-nent reactions for the synthesis of α-arylglycines using in-expensive and nontoxic bismuth and iron catalysts.16a,b
These reactions provide straightforward access to a broadscope of α-(hetero)arylglycines. They utilize readily avail-able starting materials and water is generated as the onlyby-product. Herein we report the full scope and limitationsof both methods, together with comparison of the specificadvantages and disadvantages as well as detailed mechanis-tic investigations.
Optimization and ScopeAt the onset of our studies, we hypothesized that an
ideal catalyst should be able to catalyze both the formationof a reactive N-acylimine via condensation of an amide witha glyoxylic acid derivative and the addition of an unreactive
arene to the in situ formed N-acylimine. Small quantities ofwater formed in the condensation step should not lead to asignificant catalyst deactivation. For the sake of practicalitythe glyoxalate was used in its more stable polymeric or hy-drated form.17
To identify a suitable catalyst system, the reaction ofbenzamide (1a) with commercially available ethylglyoxalate (2a)18 and the moderately reactive m-xylene(3a)19 was chosen using only 1 mol% of the catalyst (Table1). Preliminary results revealed that several Lewis andBrønsted acids are able to catalyze this reaction, albeit withvarious degrees of efficiency (Table 1). Water-sensitiveLewis acids, such as BF3·OEt2 and AlCl3, or weak Brønstedacids, for example, TFA or (PhO)2P(O)OH, did not catalyzethe reaction at all (yields <10%, results not shown).
Table 1 Initial Screening of Different Catalysts
The stronger Brønsted acids TfOH and TsOH providedthe desired product in <20% yield (Table 1, entries 6 and 8).A higher loading of TfOH did not lead to a greatly improvedyield (entry 7). Most promising results were obtained withBi(OTf)3, In(OTf)3, and Yb(OTf)3 (entries 2–4). Other metaltriflates such as Sc(OTf)3, Mg(OTf)2, or Zn(OTf)2 did notshow a similar catalytic activity. Surprisingly, 1 mol%Fe(ClO4)3 furnished the α-arylglycine 4a in 91% yield (entry1).
From an ecological and economic point of view, readilyavailable, cheap, and nontoxic iron salts would be an idealcatalyst system for this three-component reaction.20,21
Therefore, iron-based catalysts were investigated in moredetail. During our previous research on amidoalkylation re-actions, Bi(OTf)3 was identified as a very active, nontoxic,and relatively cheap catalyst.22,23 Thus, we decided to take
R2-NH2
R1 H
NR2
imine
path A: Strecker
R1 = ArNu = CN
path B: Mannich
R1 = CO2RNu = Ar-H or Ar-B(OH)2
Ar
NHR2
CN
Ar
NHR2
CO2H
hydrolysis
– H2O
path C: aza-Friedel-Crafts
R1 = CO2EtNu = (Het)Ar-H
(Het)Ar
NHR2
CO2Et
R1-CHO
+
Entry Catalyst Yield (%)a
1 Fe(ClO4)3·xH2O 91
2 Bi(OTf)3 88
3 In(OTf)3 72
4 Yb(OTf)3 54
5 Sc(OTf)3 16
6 TfOH 18
7 TfOH (5 mol%) 49
8 TsOH 12a Yields are given for the isolated product. The product was obtained as a 98:2 mixture of regioisomers. Only the major regioisomer is shown.
H CO2Et
O
++ 80 °C, 18 h
MeNO2
1a 2a
BzNH2
Me
Me
3a 4a
1 mol% cat.
CO2EtBzHN
Me
Me
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focus on bismuth-catalyzed reactions as well. AlthoughIn(OTf)3 and Yb(OTf)3 showed promising catalytic activity(Table 1, entries 3 and 4), In- and Yb-based catalysts werenot examined due to the toxicity and teratogenic potentialof In(III) and Yb(III) salts.24
To optimize the reaction conditions for both bismuth-and iron-based conversions, the initial model reaction be-tween benzamide (1a), ethyl glyoxalate (2a), and m-xylene(3a) was chosen. The results for the optimization of the ironcatalyst are depicted in Table 2. Both, iron chloride either inits anhydrous form or as hexahydrate, as well as iron per-chlorate displayed high catalytic activities. Despite the factthat both Fe(ClO4)3 and FeCl3·6H2O gave similar yieldsduring the initial optimization reactions (Table 2, entries 1and 7), Fe(ClO4)3 led to higher yields in general. Additional-ly, for Fe(ClO4)3 the catalyst loading can be decreased with-out significant loss of efficiency (entry 9). Whereas 1 mol%Fe(ClO4)3 led to the desired product in 91% yield (entry 8),the yield with 1 mol% FeCl3 dropped to 18% (entry 5). Thecorresponding Fe2+ salts could catalyze the model reaction
with similar efficiency (entries 6 and 11). However, asjudged by the observed rapid color change, we assume afast oxidation of Fe2+ to Fe3+ under our aerobic reaction con-ditions. To rule out a possible ‘hidden’ catalysis by Brønstedacids, the reaction was performed in the presence of theproton scavenger 2,6-di-tert-butylpyridine (dbpy, entry12).25 No significant decrease in yield was observed. There-fore, we concluded that a Fe3+ species is the active catalyst.
Next, different solvents were examined for our three-component reaction (Table 2, entries 13–16). Best resultswere obtained in nitromethane. All other tested solventsled to lower yields (1,2-dichloroethane, dichloromethane,or 1,4-dioxane) or complete shutdown of the reaction (THF,H2O, EtOAc). A similar screening of reaction parameters wasperformed with the Bi-catalyzed three-component synthe-sis. As shown in Table 3, Bi(OTf)3 proved to be the optimalcatalyst. Other bismuth salts like BiCl3 or BiBr3 afforded theproduct in lower yields (Table 3, entries 5 and 6). Notably,the catalyst loading of Bi(OTf)3 could be reduced to only1 mol% without a significant change in yield and even withonly 0.5 mol% of Bi(OTf)3 the product could be isolated in77%. As shown in Table 1, TfOH, a possible by-product fromthe hydrolysis of Bi(OTf)3, did not display a similar catalyticactivity. To further exclude a possible Brønsted acid cataly-sis a control reaction with the proton scavenger dbpy wasperformed also in the case of Bi(OTf)3 (entry 7). Again nosignificant decrease in the catalytic activity was observed,indicating a Bi(III)-species as the active catalyst. In the caseof the Bi-catalyzed reaction, nitromethane also proved to be
Table 2 Optimization of the Reaction Parameters for Fe-Catalyzed Three-Component Reaction for the Synthesis of α-Arylglycine 4a
Entry Catalyst Solvent Yield (%)a
1 FeCl3·6H2O (5 mol%) MeNO2 84
2 FeCl3·6H2O (2 mol%) MeNO2 84
3 anhyd FeCl3 (5 mol%) MeNO2 86
4 anhyd FeCl3 (2 mol%) MeNO2 87
5 anhyd FeCl3 (1 mol%) MeNO2 18
6 FeCl2·4H2O (2 mol%) MeNO2 82
7 Fe(ClO4)3·xH2O (5 mol%) MeNO2 91
8 Fe(ClO4)3·xH2O (1 mol%) MeNO2 91
9 Fe(ClO4)3·xH2O (0.5 mol%) MeNO2 75
10 Fe(ClO4)3·xH2O (0.1 mol%) MeNO2 37
11 Fe(ClO4)2·xH2O (2 mol%) MeNO2 82
12 Fe(ClO4)3·xH2O (5 mol%) + dbpy (10 mol%) MeNO2 86
13 FeCl3·6H2O (2 mol%) DCE 39
14 FeCl3·6H2O (2 mol%) CH2Cl2 23
15 FeCl3·6H2O (2 mol%) 1,4-dioxane <10
16 FeCl3·6H2O (2 mol%) MeCN 10a Yields are given for the isolated product. The product was obtained as a 98:2 mixture of regioisomers. Only the major regioisomer is shown.
H CO2Et
O
++
1a 2a
BzNH2
Me
Me
3a 4aCO2EtBzHN
Me
Me
80 °C, 16 hMeNO2
Fe2+/3+
Table 3 Optimization of the Reaction Parameters for Bi-Catalyzed Three-Component Reaction for the Synthesis of α-Arylgylcine 4a
Entry Catalyst Solvent Yield (%)a
1 Bi(OTf)3 (5 mol%) MeNO2 84
2 Bi(OTf)3 (2 mol%) MeNO2 89
3 Bi(OTf)3 (1 mol%) MeNO2 88
4 Bi(OTf)3 (0.5 mol%) MeNO2 77
5 BiCl3 (5 mol%) MeNO2 72
6 BiBr3 (5 mol%) MeNO2 69
7 Bi(OTf)3 (5 mol%) + dbpy (10 mol%) MeNO2 84
8 Bi(OTf)3 (5 mol%) DCE 52a Yields are given for the isolated product. The product was obtained as a 98:2 mixture of regioisomers. Only the major regioisomer is shown.
H CO2Et
O
++
1a 2a
BzNH2
Me
Me
3a 4aCO2EtBzHN
Me
Me
80 °C, 16 hMeNO2
Bi3+
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the ideal solvent. While yields in 1,2-dichloroethane werestill acceptable (entry 8), the use of other solvents led tosignificant lower yields (results not shown).
Scope of (Hetero)Arenes, Amides, and GlyoxalatesAfter identification of the ideal reaction conditions, the
scope of our methods was explored. First, reactions of dif-ferent arenes with benzamide (1a), and ethyl glyoxalate(2a) were investigated. Various electron-rich arenes aresuitable substrates for both the Fe- and the Bi-catalyzedaza-Friedel–Crafts reaction (Scheme 2). The combined re-sults are shown in Scheme 2. Both types of catalyst fur-nished different α-arylglycine derivatives in good to excel-lent yields. Interestingly N-pivalolyl-protected aniline 3mreacted chemoselectively and α-arylglycine 4m was isolat-ed in 67% (Bi) and 80% (Fe) yield. The reactions of polycyclic
arenes led to the formation of glycine derivatives 4q and 4r,useful building blocks for the synthesis of fluorescence la-bels,26 in 49–64% yield. Less reactive arenes, such as ben-zene, did not react, even under harsh reaction conditions. Inmost cases only one regioisomer was obtained. However, insome cases, such as in the reaction with anisole, a mixtureof regioisomers was isolated. To our surprise, the use ofBi(OTf)3, supposedly the more active catalyst, always led tohigher regioselectivities. In certain cases, such as withanisole, only a small, negligible difference in the regioselec-tivity was observed (75:25 vs. 71:29 para/ortho). However,for reactions with other arenes, Bi(OTf)3 furnished the de-sired products with a significantly higher regioselectivity.This fact is exemplified by the arylglycines 4e (86:14 vs.
Scheme 2 Substrate scope: arene component. Yields are given for isolated products. Unless otherwise mentioned, the corresponding α-arylglycine was observed as one single regioisomer (d.r. >98:2). In the case of regioisomers, only the major one is shown. Bz = benzoyl, Piv = pivalolyl.
H CO2Et
O+
BzHN Ar
CO2EtAr-H
Ph
O
NH2
+
1a 2a 3 4
BzHN Mes
CO2Et
BzHN
CO2Et
OMe
CO2Et
OMe
BzHN
CO2Et CO2Et
MeO
MeBzHN
CO2Et
Me OMe
BzHN BzHN
OMe
Me
Cl
4bBi3+: 95%Fe3+: 94%
4cBi3+: 75% (r.r. 75:25)Fe3+: 67% (r.r. 71:29)
4gBi3+: 77%Fe3+: 68%
BzHN
CO2Et
OMe
IBzHN
CO2Et
OMe
Br
4hBi3+: 88%Fe3+: 74%
4iBi3+: 81%Fe3+: 76%
4dBi3+: 70%
Fe3+: 68% (r.r. 94:6)
4eBi3+: 59% (r.r. 86:14)Fe3+: 63% (r.r. 75:25)
4fBi3+: 62%Fe3+: 63%
CO2Et
OMe
BzHNOMe
OMe
4oBi3+: 68%Fe3+: 58%
4rBi3+: 54%Fe3+: 57%
BzHN
CO2Et
CO2Et
MeO
CO2EtBzHN
4nBi3+: 40%Fe3+: 66%
BzHN
CO2Et
MeO
4qBi3+: 49%Fe3+: 64%
OMe
Me Me
CO2EtBzHN
4pBi3+: 50% (r.r. 67:33)Fe3+: 62% (r.r. 50:50)
CO2Et
BzHN
MePivHN
4mBi3+: 67% (r.r. 95:5)
Fe3+: 80% (r.r. 71:29)
BzHN
CO2Et
4sBi3+: 0%Fe3+: 0%
BzHN
CO2Et
MeO
BrBzHN
CO2Et
MeO
I
4jBi3+: 41%Fe3+: 34%
4kBi3+: 59%Fe3+: 50%
BzHN
CO2Et
Me
Me
4lBi3+: 40%Fe3+: 32%
1–5 mol%Bi3+ or Fe3+
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75:25), 4m (95:5 vs. 71:29), or 4p (67:33 vs 50:50). So farwe do not have a conclusive explanation for this phenome-non.
Next, the reactions of different amides and carbamateswith ethyl glyoxalate (2a) and mesitylene (3b) were exam-ined (Scheme 3). To our delight different benzamide deriva-tives were compatible with both catalysts systems and thedesired products 5a–c were obtained in excellent yields(68–94%). Alkyl-substituted primary amides are also suit-able substrates and arylglycine derivatives 5d–f were ob-tained in 70–88% yield with iron catalysis and in 79–81%yield with bismuth catalysis. Even acid-sensitive amidessuch as acrylamide were transformed into the desired prod-uct 5g in 82% (Bi) or 85% (Fe) yield. Carbamates are suitablesubstrates for the bismuth- and the iron-catalyzed three-component reactions. Different N-protected α-arylglycines5h–k, such as 5i bearing a Cbz-protecting group or theFmoc-derivative 5k, were obtained in high yields. Unfortu-nately reaction with tert-butyl carbamate did not furnishthe desired Boc-protected arylglycine 5l. Sterically moredemanding secondary amides or electron-deficient trifluo-roacetyl amide proved to be unsuitable for our method andthe desired products 5m and 5n could not be obtained.
Not only arenes but also heteroaromatic compounds aresuitable substrates for the three-component reaction(Scheme 4). The corresponding heteroarylglycines 7a–lwere obtained in good to excellent yields with both Fe andBi catalysis. In general, lower reaction temperatures werenecessary to avoid direct addition of the heteroarene to thealdehyde (Scheme 5).27 Reaction of benzamide (1a) withethyl glyoxalate (2a) and a heteroarene 6 as the nucleophil-ic component furnished different heteroarylglycines in 47to 88% yield (Scheme 4). Interestingly, reactions with carba-mates, such as urethane, as the amide component, led tooverall higher yields as well as improved regioselectivities.Improved regioselectivities can be rationalized by the de-creased reactivity of the in situ formed N-carbamoyliminecompared to the N-acylimine in the benzamide case. Thelow yields with benzamides are most probably associatedwith the instability of the formed amidoalkylated productsunder acidic conditions. We assume that these compoundsdecompose under acidic conditions via dissociation of thebenzamide, thereby forming a stabilized heterobenzyliccation 9, which can react with excess of the heteroarene tothe corresponding diarylmethane derivative 10.
Scheme 3 Substrate scope: amide component. Yields are given for the isolated products. Mes = mesityl (2,4,6-trimethylphenyl), Bn = benzyl, Fmoc = [9H-fluoren-9-yl)methoxy]carbonyl.
Me NH
O
Mes
CO2Et
NH
O
Mes
CO2Et
t-Bu NH
O
Mes
CO2Et
NH
O
MeO
Mes
CO2Et
EtO NH
O
Mes
CO2Et
BnO NH
O
Mes
CO2Et
R
O
NH2
+H CO2Et
O+
R
O
NH
Mes
CO2EtMe
Me Me
1 2a 3b 5
O NH
O
Mes
CO2Et
FmocNH
Mes
CO2Et
5aBi3+: 81%Fe3+: 94%
5eBi3+: 79%Fe3+: 70%
NH
O
Br
Mes
CO2Et
5bBi3+: 80%Fe3+: 85%
NH
O
O2N
Mes
CO2Et
5cBi3+: 68%Fe3+: 89%
5fBi3+: 81%Fe3+: 80%
NH
O
Mes
CO2EtCl
5dBi3+: 81%Fe3+: 88%
5gBi3+: 82%Fe3+: 85%
5hBi3+: 86%Fe3+: 83%
5iBi3+: 65%Fe3+: 51%
5jBi3+: 84%Fe3+: 70%
5kBi3+: 83%Fe3+: 75%
O NH
O
Mes
CO2EtPh N
O
Mes
CO2Et
5lBi3+: 0%Fe3+: 0%
F3C NH
O
Mes
CO2Et
5mBi3+: 0%Fe3+: 0%
5nBi3+: 0%Fe3+: 0%
1–5 mol%Bi3+ or Fe3+
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Indeed, Bi(OTf)3-catalyzed reactions of very electron-rich heterocycles, such as benzofuran, N-tosylpyrrole, or-indole, with benzamide (1a) and ethyl glyoxalate (2a) ledto the selective formation of the double addition productsof type 10 (Scheme 5). Using the less active iron catalyst,heteroarylglycines 7g, 7i, and 7k could be isolated in 51, 62,and 74% yield, respectively. Both methods are not limited toethyl glyoxalate as the aldehyde component (Scheme 6).28
Reactions with different glyoxalates, such as isopropyl gly-oxalate (2b) furnished the desired amino acid derivative11a in 50 and 83% yield. Even free glyoxylic acid, used asaqueous solution, can be employed as aldehyde source,thereby providing the free acid 11b in 71 and 81% yield. Re-actions with carbamates, such as urethane or the Fmoc-derivative, afforded the N-protected arylglycines 11c and11d in 45–92% yield. Especially, the Fmoc-protected acid11d would be an ideal starting material for solid-phasepeptide synthesis with unnatural amino acid derivatives. Inthe case of the carbamates, iron catalysis proved to be morereliable and furnished the desired products in higher yieldsand purity.
Scheme 6 Reaction of benzamide (1a) and different carbamates with glyoxylic acid derivatives 2 and mesitylene (3b). Yields are given for iso-lated products.
LimitationsIn general, similar yields were obtained with bismuth
and iron catalysis. In the case of competing regioisomer for-mation, reactions with Bi(OTf)3 gave consistently higher re-gioselectivities. During our studies on the scope of the
Scheme 4 Substrate scope: heteroarenes. Yields are given for isolated products. Unless otherwise mentioned, the corresponding α-arylglycine was observed as one single regioisomer (d.r. >98:2). Yields are given for the isolated product. In the case of regioisomers, only the major one is shown. Ts = tosyl.
+H CO2Et
O
HetAr
CO2Et
HetAr-HNH
1 2a 6 7
R NH
O CO2Et
S
R NH
O CO2Et
S
CO2Et
S
R NH
O CO2Et
N
R NH
O CO2Et
O
NH
R
O
R NH
O CO2Et
N
Ts
7a: R = PhBi3+: 55%Fe3+: 60%
7e: R = PhBi3+: 64% (r.r. 89:11)Fe3+: 47% (r.r. 88:12)
7b: R = OEtBi3+: 77%Fe3+: 74%
7f: R = OEtBi3+: 72%
Fe3+: 78% (r.r. 93:7)
7c: R = PhBi3+: 37%
Fe3+: 50% (r.r. 63:37)
7d: R = OEtBi3+: 52%Fe3+: 75%
7g: R = PhBi3+: <5%Fe3+: 51%
7h: R = OEtBi3+: 88%
Fe3+: 75% (r.r. 80:20)
7i: R = PhBi3+: <5%Fe3+: 62%
7j: R = OEtBi3+: 62%Fe3+: 75%
7k: R = PhBi3+: <5%
Fe3+: 74% (r.r. 82:18)
7l: R = OEtBi3+: 78%Fe3+: 83%
Br Cl MeTs
O
RR
O
NH2
2–5 mol%Bi3+ or Fe3+
+
Scheme 5 Mechanistic rationale for the formation of the observed by-products with very electron-rich (hetero)arenes
H CO2Et
O
(Het)Ar CO2Et
HO
(Het)Ar-H (Het)Ar CO2Et
H (Het)Ar-H
(Het)Ar CO2Et
(Het)ArL.A. L.A.Bi3+ or Fe3+
2a 8 9 10
– H2O
(Het)Ar CO2Et
NHBz
4, 7 or 12
– Bz-NH2
NH
Mes
CO2H
R
O
NH2
+H CO2R'
O+
Bi3+ or Fe3+
NH
Mes
CO2R'
1 2 3b 11
11bBi3+: 71%Fe3+: 81%
NH
Mes
CO2HO
EtOBz
NH
Mes
CO2H
FmocNH
Mes
CO2i-Pr
11aBi3+: 50%Fe3+: 83%
11cBi3+: 50%Fe3+: 92%
11dBi3+: 45%Fe3+: 85%
Bz
Mes-H
O
R
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arene component, a significant difference was observed inthe reactivity for very electron-rich as well as for unreactivearomatics (Scheme 7). These differences in reactivity aremost probably associated with the activity of the used cata-lyst. For very reactive, electron-rich arenes, such as dimeth-oxybenzenes, anthracene, or anisidine derivatives, the lessactive iron catalyst proved to be advantageous. The amido-alkylated arenes 12a–j were obtained in 63–89% yield. Re-actions of electron-rich arenes in combination with themore active Bi(OTf)3 gave the corresponding products inlower yields or did not afford the product at all. In thesecases, the competing formation of diarylmethane deriva-tives was observed in significant quantities (cf. Scheme 5).For free phenols, such as 4-bromophenol, bismuth catalysisproved to be advantageous and furnished the glycine deriv-ative 12g in 65% yield (vs 11% with Fe3+). With iron catalystsoxidative coupling reactions of the phenol were observed.In the case of less reactive arenes, such as o-xylene, themore active bismuth catalyst proved to be more efficientand afforded the arylglycine in 89% yield (vs 54% with Fe3+
catalysis). Bi(OTf)3 could even catalyze the reaction of tolu-ene, furnishing product 12j in 50% yield. In the case of ironcatalysis no product formation was observed with toluene.Although the lower catalytic activity of the iron salts mightlook like a disadvantage at the first glance, it proved to be a
major advantage in terms of practicability. Commerciallyavailable, technical ethyl glyoxalate, is commonly providedas a solution of the polymer form in toluene. In the case ofBi-catalyzed reactions, toluene has to be removed prior tothe reaction to avoid the formation of 12j as side-product.For iron-catalyzed reactions the commercially availablesolution can be used without further processing, therebyleading to a more straightforward procedure.
Also in the case of less reactive amide components, thehigher catalytic activity of Bi(OTf)3 proved to be beneficial(Scheme 8). Bi(OTf)3-catalyzed reactions with cyclic sec-ondary amides or carbamates afforded the desired products14a and 14b in 63 and 80% yield. No product formation
Scheme 7 Substrate scope: limitation for Bi3+ and Fe3+. Yields are given for the isolated products. Unless otherwise mentioned, the corresponding α-arylglycine was observed as one single regioisomer (d.r. >98:2). In the case of regioisomers, only the major one is shown.
BzHN
CO2Et
NHPiv
MeO
BzHN
CO2Et
OMe
NHPiv
BzHN CO2Et
BzHN
CO2Et
Me
Me
12hBi3+: 89% (r.r. 89:11)Fe3+: 54% (r.r. 80:20)
BzHN
CO2Et
Me
12jBi3+: 50% (r.r. 75:25)
Fe3+: 0%
BzHN
CO2Et
Cl
MeO
12iBi3+: 89%Fe3+: 34%
BzHN
CO2Et
Br
HO
12gBi3+: 65%Fe3+: 11%
12aBi3+: 62%Fe3+: 89%
12bBi3+: 0%
Fe3+: 80% (r.r. 67:33)
12fBi3+: 48%Fe3+: 82%
BzHN
CO2Et
OMe
MeO
12dBi3+: 0%
Fe3+: 74%
BzHN
CO2Et
12eBi3+: 0%
Fe3+: 63%
BzHN
CO2Et
Me
NHPiv
12cBi3+: 45%
Fe3+: 77% (r.r. 91:9)
H CO2Et
O+
Fe3+ or Bi3+
BzHN Ar
CO2EtAr-H
Ph
O
NH2
+
1a 2a 3 12
OMe
OMe
Scheme 8 Substrate scope: reactions with cyclic secondary amides and carbamates. Yields are given for the isolated products.
N Mes
CO2Et+
H CO2Et
O+
2–5 mol%Bi3+ or Fe3+
2a 3b 14
14bX = O
Bi3+: 80%Fe3+: 0%
X
O
X NH
O
14aX = CH2
Bi3+: 63%Fe3+: 8%
13
Mes-H
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with iron catalysts was observed. Acyclic secondary amidesor carbamates proved to be unreactive using either bismuthor iron catalysis.
Interestingly, Bi(OTf)3 was able to catalyze reactionswith different sulfonamides as amide component (Scheme9). The corresponding N-sulfonylated arylglycines 16a–cwere obtained in 54–79% yield. Presumably, Bi(OTf)3 is ac-tive enough to catalyze the addition of arenes to in situ lesselectrophilic N-sulfonylimines.14
Scheme 9 Substrate scope with sulfonamides. Yields are given for the isolated products.
Investigations into Stereoselective ReactionsSince most of the natural α-arylglycines exist in one en-
antiomeric form, stereoselective synthesis of these com-pounds would be highly desirable. Therefore, we decided toinvestigate a possible asymmetric version of our three-component reactions (Scheme 10). The most obvious ap-proach would be the use of chiral ligands in our transforma-tion. Hence various common chiral ligands were tested incombination with different Bi3+ or Fe3+ salts (Scheme 10).29
Unfortunately, no asymmetric induction was observed us-ing various metal–ligand combinations, solvents, or tem-peratures (Scheme 10). In further studies using different li-gands and variations of the amide or arene component aswell as In3+ and Yb3+, promising Lewis acids in our initialscreening, were studied. Again no asymmetric inductionwas observed.
Scheme 10 Unsuccessful enantioselective approaches
Since no enantioselective version of the three-compo-nent reaction could be realized with chiral catalysts, we de-cided to explore diastereoselective reactions with chiralamide components (Schemes 11–13).
For first tests chiral carbamates based on the Evans aux-iliary were selected (Scheme 11).30 However, chiral oxazo-lidinones, such as 20a or 20b, did not furnish the desiredproducts under our standard reaction conditions. Whereas20b did not react at all, an interesting reactivity was ob-served for oxazolidinone 20a. The bismuth-catalyzed reac-tion of 20a furnished cyclic amino acid derivative 21 in 84%yield as single diastereomer (Scheme 12). Formation of thecyclic product can be rationalized by an intramolecular ad-dition of the phenyl moiety to the formed N-acylimine.Even in the presence of excess of mesitylene no intermolec-ular addition was observed. Therefore, we next selectedchiral primary amides as potential chiral starting materialsfor our three-component reaction.
Scheme 11 Unsuccessful diastereoselective approach using Evans-type carbamates
Reaction of phthalimide-protected valine amide 22with ethyl glyoxalate (2a) and mesitylene (3b) furnishedthe expected product 23 in 84% with Bi(OTf)3 and 78% yieldwith FeCl3·6H2O (Scheme 13). Only moderate diastereose-lectivities (67:33 and 65:35) were observed. Variation ofthe temperature, solvent, or catalyst did not improve thestereoselectivity. Replacing the amide protecting group by acarbamate, led to a diminished diastereoselectivity and adrastic decrease in isolated yields. Reactions with amide-protected valine amides did not furnish any desired prod-uct at all. In summary, all our approaches to stereoselectivereactions did not lead to the expected results. Only in thecase of chiral amide components moderate stereoselectivi-
RS
O
NH2
O
H
O
CO2Et RS
O
NH
O
Mes
CO2Et
Mes-H2 mol% Bi(OTf)3
MeNO280 °C, 16 h
15 2a 16
MeS
O
NH
O
Mes
CO2Et
16aFe3+: 0%Bi3+: 54%
S
O
NH
O
Mes
CO2Et
R
16bR = Me: 79%R = Br: 54%
R = OMe: 64%
S
O
NH
O
Mes
CO2Et
16c67%
S
3b
+ +
N
OO
N
Me
R R
Me
N
OO
NR R
N
N
OO
N
R R
H CO2Et
O+
BzHN Mes
CO2Et
1a 2a
BzNH2
3a 4a0% ee
Mes-H
metal saltsligands
different conditions
17 18 19
+
O NH
O
R
H
O
CO2EtMes-H O N
O
R
CO2Et
Mes
R = Bn: 0%R = i-Pr: 0%
2 mol% Bi(OTf)3
80 °C, 16 hMeNO2
20 2a 3b
+ +
Scheme 12 Intramolecular amidoalkylation of 20a. Yield is given for the isolated product.
O NH
O
H
O
CO2Et
2 mol% Bi(OTf)3
80 °C, 16 hMeNO2
CO2Et
NO
O
2a20a84%21
Ph
+
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ties could be achieved. Therefore, further studies into thefield of asymmetric three-component reactions were notpursued.
Scheme 13 Reaction of N-protected valine amide 22. Yields are given for the isolated products. Phth = phthaloyl, PG = protecting group.
Mechanistic InvestigationsIn order to gain further insight into the reaction mecha-
nism and the different catalytic activities of Bi(OTf)3 andFe3+ salts, a series of experiments were performed. First theprogress of the reaction between benzamide (1a), ethyl gly-oxalate (2a), and mesitylene (3b) in the presence of differ-ent catalysts as well as catalyst loadings was monitored bygas chromatographic analysis (Scheme 14, Figures 2 and 3).
Scheme 14 Model reaction for kinetic experiments
In order to obtain a clearer distinction between the dif-ferent systems, the reaction was performed at a slightly de-creased temperature of 60 °C. Initially we compared therates for conversion of the limiting starting material, ben-zamide (1a), and product formation with 5 mol% of Bi(OTf)3
and 5 mol% Fe(ClO4)3. In both cases an interesting observa-tion was made: the rates of benzamide conversion andproduct formation deviate significantly from each other atthe onset of the reaction (Figure 2).
In the case of Fe(ClO4)3, a fast conversion of the benz-amide (20% conversion after 10 min and 70% after 45 min)was observed. However, the rate of product formation wasslower (<1% yield after 10 min and 50% yield after 45 min).Similar observations were made with 5 mol% of Bi(OTf)3(20% and 45% conversion vs 2% yield and 30% yield after 10and 45 min, respectively). Since in both cases the yield of α-arylglycine 4b exceeded 90% after 24 hours reaction time,no unproductive side-reactions of benzamide can accountfor the fast conversion of the amide component. Therefore,formation of some kind of productive intermediate, mostprobably by the reaction of two of the three components,has to take place.
As can be seen from Figure 3, Fe(ClO4)3 catalyzes the re-action with a higher efficiency than Bi(OTf)3, both at high(5 mol%) and low (1 mol%) catalyst loading. With 5 mol%Fe(ClO4)3 64% of the amidoalkylated product is observed af-ter 60 minutes, compared to only 28% with 5 mol% Bi(OTf)3.As expected, reduction of the catalyst loading to 1 mol%leads to a considerable decrease in the reaction rate (Figure3).
Interestingly, FeCl3·6H2O displays the lowest catalyticactivity. After 50 minutes at 60 °C, only 5% product forma-tion was observed with 5 mol% FeCl3·6H2O. Presumably, afacile dissociation of the noncoordinating counterions toform an active metal catalyst is crucial for a high activity.31
We have to emphasize that under our standard reactionconditions (80 °C; 16 h, 24 h, respectively) all three cata-lysts [Fe(ClO4)3, FeCl3·6H2O, and Bi(OTf)3] give similar yieldsat 5 mol% and even 2 mol% loadings (>90% in all cases). Toour surprise, Bi(OTf)3, the catalyst with the best perfor-mance with less reactive arenes, displayed an inferior activ-ity compared to Fe(ClO4)3 in the reaction with mesitylene
+H
O
CO2Et+ Mes-H
2 mol% Bi(OTf)3
80 °C, 16 hMeNO2
iPr
N
O
NH2
2322 2a 3b
NH
ONH
iPr
Mes
EtO2C
PG
PG
PG = Phth: 2 mol% Bi(OTf)3: 87%, d.r. 67:332 mol% FeCl3: 78%, d.r. 65:35PG = Cbz: <10%, d.r. 50:50
H CO2Et
O++
60 °CMeNO2
1a 2a
BzNH2
3b 4b
1–5 mol% Bi3+ or Fe3+
Mes-HBzHN Mes
CO2Et
Figure 2 Comparison of the rates of benzamide conversion and product formation
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(Figure 3). Therefore, Fe(ClO4)3 is the catalyst of choice formore reactive arenes, considering the activity and the eco-nomic and ecologic aspects of iron(III) salts.
As outlined in the introduction, our first rationale forthe development of these three-component reactions wasthe in situ formation of a reactive N-acylimine species. Ini-tial experiments indicated the formation of a two-compo-nent adduct of benzamide with one of the other startingmaterials (Figure 2). Therefore, we examined the reactionbetween benzamide (1a) and ethyl glyoxalate (2a) in thepresence of 5 mol% Fe(ClO4)3 or 5 mol% Bi(OTf)3(Scheme 15). At room temperature quantitative formationof N,O-hemiaminal 24a is observed within 24 hours(Scheme 15). Longer reaction times (96 h) or heating to80 °C led to the formation of bisamide 25a, insoluble inmost common organic solvents, in almost quantitativeyields. Indeed, the formation and precipitation of bisamide25 could be observed in some of our three-component re-actions. During the reaction bisamide 25a is consumedcompletely and at the end the reaction mixture becomeshomogenous again. Due to the insolubility of bisamide 25aand the instability of bisamide 25a and hemiaminal 24a,we were not able to quantify the amount of both interme-diates during the course of the reaction with the analyticalmethods available at our department (GC, HPLC, React-IR,or NMR). Neither were we able to detect any reactive N-acylimine species.32 As expected, the reaction of benzamide(1a) and mesitylene (3b) in the presence of an iron or bis-muth catalyst did not furnish any new product at all(Scheme 15). Treatment of either hemiaminal 24a or bis-amide 25a, both known precursors for acylimines,14 withBi(OTf)3 or Fe(ClO4)3 and mesitylene (3b) led to the expect-ed formation of the aryl glycine derivative 4b in 85 and 83%yield. To elucidate further reaction pathways, the two-com-
ponent reaction of mesitylene (3b) with ethyl glyoxalate(2a) was investigated next. Both 2 mol% Bi(OTf)3 and2 mol% Fe(ClO4)3 furnished the double addition product 26in 70–74% yield. Formation of such diarylmethane productswas already observed in the case of more reactive (hete-ro)arenes (cf. Scheme 5) and is described in the literature.27
Addition of a ligand, 2,2′-bipyridine (bipy) to the iron-cata-lyzed reaction, enabled the controlled synthesis ofmonoaddition product 27 in 66% yield. Alcohol 27 is thepresumed intermediate in the synthesis of diarylmethaneproducts of type 26. We next examined alcohol 27 as a pos-sible intermediate in our three-component reaction. Treat-ment of 27 with 1.0 equivalent of benzamide and2.0 equivalents of mesitylene under our standard reactionconditions did furnish the expected product 4b and diaryl-methane derivative 26 in less than 5% yield, using eitherBi(OTf)3 or Fe(ClO4)3. These experiments indicate that alco-hol 27 is not involved in the main reaction pathway. On thebasis of these results, we assume the following mechanism(Scheme 15). In the first step, the amide adds to the glyox-ylic acid derivative 2 to form hemiaminal 24. Elimination ofwater furnishes a reactive acylimine species 28. Trapping ofthis highly electrophilic imine with a second molecule ofthe amide gives bisamide 25, observed intermediate insome of our three-component reactions. The fast additionof a second amide is not surprising, if one considers thehigher nucleophilicity of the amide nitrogen.18 Under thereaction conditions, bisamide 25, favored under kineticcontrol, can decompose to yield the reactive N-acylimine28. In the presence of a suitable, nucleophilic arene, the N-acylimine can undergo an aza-Friedel–Crafts type reactionto afford the desired α-arylglycine product 4 containing athermodynamically more stable C–C bond. The catalytic ac-tivity of the used catalyst greatly depends on two factors.On the one hand, the catalyst has to be stable in the pres-ence of significant amounts of water, since up to 100 equiv-alents of water are generated during the course of the reac-tion (with respect to the catalyst).
On the other hand the catalyst has to promote the addi-tion of the amide 1 to the glyoxalate 2 over the direct addi-tion of the arene 3 to the aldehyde 2. Only the right combi-nation of both reactivities leads to an efficient catalyst forthese three-component reactions. In addition, the Lewisacidic catalyst could further activate the N-acylimine to-wards the addition of a nucleophile. This might partially ex-plain the higher activity of Bi(OTf)3, a strong Lewis acid, inreactions with less nucleophilic arenes.28 Another possibleexplanation for the high catalytic efficiency of bismuth aswell as the observed improved regioselectivities is the acti-vation of the arene component by the bismuth catalyst. Al-though Bi(III)-arene complexes have been reported in liter-ature, we do not have any solid experimental evidence foran additional activation of the arene component.33 We as-sume that two factors contribute to the observed low stereo-selectivities in our asymmetric approaches. The high intrin-
Figure 3 Rates of product formation with different catalyst loadings
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Scheme 15 Mechanistic studies and postulated reaction pathway
MesMesMesMes-H
Mes
+Bi3+ or Fe3+
Ph
O
NH2
1a1.0 equiv
H
O
CO2Et r.t., 24 hMeNO2
2a1.2 equiv
Ph
O
NH
OH
CO2Et r.t., 96 h Ph
O
NH
CO2Et
NH
O
Ph
24aN,O-hemiaminal
>95%
25abisamide
+Bi3+ or Fe3+
Ph
O
NH2
1a2.0 equiv
H
O
CO2Et 80 °C, 24 hMeNO2
2a1.0 equiv
Ph
O
NH
CO2Et
NH
O
Ph
25abisamide
>95%
Lewis acid (L.A.)
R
O
NH2
1H
O
CO2R'2
R
O
NH
OH
CO2R'
24N,O-hemiaminal
Lewis acid (L.A.)
– H2O
R
O
N CO2R'
28N-acylimine
R
O
NH
CO2R'
NH
O
R
+
3
NH
CO2R'
(Het)Ar
4arylglycine
elimination
H
O
CO2Et 80 °C, 24 hMeNO2
2a1.0 equiv
+
3b2.5 equiv
CO2Et
H
O
CO2Et 80 °C, 24 hMeNO2
2a1.0 equiv
+
3b2.5 equiv
2 mol% Fe(ClO4)3
3 mol% bipy OH
CO2Et
262 mol% Bi(OTf)3: 70%
2 mol% Fe(ClO4)3: 74%
2766%
25bisamide
Ph
O
NH
OH
CO2Et
24aN,O-hemiaminal
Ph
O
NH
CO2Et
NH
O
Ph
25abisamide
BzHN
CO2Et
BzHN
CO2EtBi3+ or Fe3+
4b5 mol% Bi(OTf)3: 85%
5 mol% Fe(ClO4)3: 83%
4b5 mol% Bi(OTf)3: 79%
5 mol% Fe(ClO4)3: 78%
Bi3+ or Fe3+
OH
CO2Et
271.0 equiv
+Ph
O
NH2
1a1.0 equiv
+
3b2.0 equiv
80 °C, 24 hMeNO2
CO2Et+
BzHN
CO2Et
4b<5%
26<5%
5 mol% Bi(OTf)3 or5 mol% Fe(ClO4)3
+Bi3+ or Fe3+
Ph
O
NH2
1a1.0 equiv
3b3.0 equiv
no conversionobserved
+/–R NH2
O
+ H2O
(Het)Ar-H
O
R
(Het)Ar-H3
BzHN
CO2Et
Mes
4b1.0 equiv
+
3b3.0 equiv
L.A.
L.A.
fast equilibrium
slowrate-determining stepfast
additionfast
1
Postulated Mechanism:
Bi3+ or Fe3+
80 °C, 18 hMeNO2
80 °C, 18 hMeNO2
+
80 °C, 24 hMeNO2
5 mol%Bi3+ or Fe3+ CO2Et
266%
BzHN
CO2Et+
4b
Mes-H
MesMes
MesMesMes-H Mes-H
Mes
Mes MesMesMes-H
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sic reactivity of N-acylimines leads to a low selectivity ingeneral, both for the diastereoselective and enantioselec-tive reactions. As reported in the literature, coordination ofa Lewis acid to the N-acylimine takes place at the oxygenatom.34 This places the catalyst far away from the reactivecenter, thereby severely hampering any stereochemical in-duction by the ligand. Based on this assumption, one canrationalize that tailor-made sterically very demanding li-gands should offer a solution to this problem. However, thecatalytic activity of such encumbered systems might be toolow for these types of multicomponent reactions.
Conclusion and OutlookIn summary, two general Bi(OTf)3- and Fe3+-catalyzed
three-component reactions between amides, (hete-ro)arenes, and glyoxylic acid derivatives have been devel-oped. Scope and limitations as well as advantages and dis-advantages of both catalyst systems were investigated indetail. These investigations show that very cheap Fe3+ saltsare the catalysts of choice in most reactions. The lower ac-tivity of iron-based catalysts offers an additional advantagein the case of very reactive arene components. On the otherhand, the high activity of Bi(OTf)3 significantly expands thescope of the three-component reaction and allows the utili-zation of less reactive arenes and sulfonamides. Investiga-tions into potential asymmetric versions of the three-com-ponent reaction were unsuccessful. No enantioselective re-action was realized and the diastereoselective inductionwith chiral amide components was low to moderate. Mech-anistic investigations indicate a reaction pathway via for-mation of a reactive, highly electrophilic acylimine followedby an aza-Friedel–Crafts-type reaction with the arene asnucleophilic component. These practical and operationallysimple reactions enable the efficient and straightforwardsynthesis of N-protected arylglycines from simple commer-cial available starting materials and nontoxic catalysts.With water as the only generated side-product, these meth-ods constitute a promising approach towards the sustain-able synthesis of important α-amino acids.
For reactions and column chromatography, solvents were obtainedfrom different commercial suppliers in >97% purity and used as re-ceived.All reactions were performed without any precautions to exclude am-bient air or moisture. TLC was performed on precoated aluminumsheets (silica gel 60 F254). The spots were visualized by using UV ra-diation, I2, or cerium(IV) ammonium molybdate. Flash column chro-matography was performed by using Silica 60 (0.04–0.063 mm, 230–400 mesh). All yields refer to isolated yields of compounds estimatedto be >95% pure, as determined by 1H NMR spectroscopy. Meltingpoints are uncorrected.N-(m-Tolyl)pivalamide, N-(3-methoxyphenyl)pivalamide, 1-methoxy-3,5-dimethylbenzene, 2-methoxy-naphthalene, 1-tosyl-1H-pyrrole,1-tosyl-1H-indole, N-(o-tolyl)pivalamide, N-(2-methoxy-phenyl)piv-alamide, N-(4-methoxyphenyl)pivalamide, methanesulfonamide, 4-methylbenzenesulfonamide, 4-methoxybenzenesulfonamide, 4-bro-
mobenzenesulfonamide, thiophene-2-sulfonamide, and 2-(1,3-diox-oisoindolin-2-yl)-3-methylbutanamide were synthesized accordingto literature.16 Ethyl glyoxalate was obtained as 50 wt% solution in tol-uene. Glyoxylic acid was obtained as 50 wt% solution in H2O and usedas received. All other starting materials were purchased from com-mercial sources and used without further purification. Fe(ClO4)3 wasobtained as undefined hydrate (Fe(ClO4)3·xH2O, yellow form, reagentgrade) from different providers. The exact H2O content was deter-mined by elemental analysis. Depending on the provider and storagetime (or even the time for weighting out a defined amount for ele-mental analysis) Fe(ClO4)3 contained from one up to ten molecules ofH2O. Therefore, the amount of Fe(ClO4)3 used is always calculated onanhyd Fe(ClO4)3. No changes in catalytic activity were observed fordifferent batches of Fe(ClO4)3 or upon prolonged storage times. Nospecial precautions were taken to avoid exposure of Fe(ClO4)·xH2O tomoisture. Caution! Perchlorate salts are known to be shock-sensitiveand are potential explosives. They should be handled with care andthe necessary precautions. Since most of these properties are associ-ated with anhyd perchlorate salts, we strongly advise to use the hy-drated form of Fe(ClO4)3. Under no circumstances should Fe(ClO4)3be dried or handled in its anhydrous form. Since similar yields areobtained even with the decahydrate Fe(ClO4)3·10H2O, this is not nec-essary. Special precautions should be taken to avoid accidental dryingof the perchlorate, for example, by accidental evaporation of the sol-vent from the reaction. During our studies we never encounteredproblems associated with Fe(ClO4)3. Even prolonged heating ofFe(ClO4)3 in MeNO2 up to 120 °C did not lead to any decomposition.(In fact it is known the anhydrous LiClO4 is stable in Et2O at tempera-tures up to 140–150 °C. For further information on perchlorate safetyand stability, we recommend the article of Long.35
Anhyd Bi(OTf)3 was obtained from different providers and used di-rectly. No special precautions were taken to avoid exposure ofBi(OTf)3 to moisture. Therefore, we cannot rule out the formation ofBi(OTf)3·xH2O during storage. Indeed, depending on the provider andstorage time (or even the time for weighting out a defined amount forelemental analysis) Bi(OTf)3 contained up to six molecules of water.However, no changes in catalytic activity and yield even upon pro-longed storage (>1 year) were observed. Therefore, the amount ofBi(OTf)3 used is always calculated on anhyd Bi(OTf)3. The actual cata-lyst loading for particular reactions might be slightly lower, depend-ing on the batch quality and storage time.1H and 13C NMR spectra were recorded at 300, 400, or 500 MHz and75, 101, or 126 MHz, respectively. Chemical shifts are reported as δ-values relative to the residual CDCl3 or DMSO-d6 peak (δ = 7.26 for 1Hand δ = 77.16 for 13C; δ = 2.50 for 1H and δ = 39.52 for 13C). Couplingconstants (J) are given in Hz and standard abbreviations are used forsignal multiplicities.Mass spectra (MS) were measured using ESI (electrospray ionization)techniques. High-resolution mass spectra (HRMS) were measured us-ing MALDI (Matrix-assisted Laser Desorption/Ionization) techniques.IR spectra were recorded on an FTIR (Fourier transform infrared spec-troscopy) spectrophotometer including a diamond universal ATRsampling technique (attenuated total reflectance) from 4000–400cm–1. The absorption bands were reported in wave numbers (cm–1).
Three-Component Synthesis of α-Arylglycines; General Procedure (GP)A 10 mL screw cap vial was charged with the respective iron salt (1–5 mol%) or Bi(OTf)3 (1–5 mol%), the appropriate amide (1.0 equiv),and MeNO2 (4.0 mL/mmol amide) (or DCE wherever applicable). Ethylglyoxalate (1.2 equiv) and the appropriate aromatic compound
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(3.0 equiv) were added under vigorous stirring. Ethyl glyoxalate wasused as a 50 wt% solution in toluene (technical form) and used as re-ceived for the reactions with iron(III) salts. For the reaction withBi(OTf)3 toluene was removed in vacuo (1 mbar, 3 h) in order to avoidside reactions. The resulting oil was redissolved in MeNO2. The reac-tion mixture was heated to 40–100 °C and stirred at this temperature.After cooling to r.t., the reaction mixture was diluted with EtOAc andfiltered through a short plug of Celite and silica gel. The plug wasrinsed with additional EtOAc. The combined filtrates were concen-trated under reduced pressure. Purification of the crude residue bycolumn chromatography (cyclohexane/EtOAc, then n-hexane/EtOAc)afforded the analytically pure product.
Ethyl 2-Benzamido-2-(2,4-dimethylphenyl)acetate (4a)Bi Catalysis: Compound 4a was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), m-xylene (0.37 mL, 3.0 mmol, 3.0 equiv), andBi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reactionmixture was stirred for 24 h at 80 °C. Purification by chromatography(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid [276mg, 89%; ratio of regioisomers (r.r.) = >98:2].Fe Catalysis: Compound 4a was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), m-xylene (0.18 mL, 1.5 mmol, 3.0 equiv), andFe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorlesssolid (141 mg, 91%; r.r. = >98:2). Further purification of the major re-gioisomer could be achieved by precipitation from hexane/CH2Cl2(only major regioisomer, as judged by 1H NMR). Analytical data wereobtained for this purified regioisomer.Mp 98.2 °C; Rf = 0.54 (cyclohexane/EtOAc = 7:3).IR (ATR): 3304 (w), 2985 (w), 2360 (w), 1745 (s), 1635 (s), 1601 (w),1580 (w), 1523 (s), 1487 (m), 1371 (w), 1348 (m), 1324 (w), 1212 (s),1189 (m), 1150 (m), 1095 (m), 1021 (m), 929 (w), 872 (w), 810 (w),774 (w), 722 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 5.3, 3.3 Hz, 2 H), 7.52–7.40(m, 3 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.07–6.96 (m, 3 H), 5.93 (d, J = 7.1 Hz,1 H), 4.31–4.11 (m, 2 H), 2.52 (s, 3 H), 2.30 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3): δ = 171.8, 166.7, 138.4, 136.9, 133.9,132.5, 131.9, 131.8, 128.7, 127.33, 127.3, 126.4, 62.0, 53.5, 21.2, 19.6,14.2.MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:312.1596.
Ethyl 2-Benzamido-2-mesitylacetate (4b)Bi Catalysis: Compound 4b was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid(308 mg, 95%).Fe Catalysis: Compound 4b was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), andFeCl3·6H2O (3 mg, 0.010 mmol, 2 mol%) in MeNO2 (2.0 mL). The reac-
tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorlesssolid (153 mg, 94%). Mp 77.6 °C; Rf = 0.50 (cyclohexane/EtOAc = 7:3)IR (ATR): 3320 (m), 2980 (w), 1727 (s), 1632 (s), 1579 (m), 1525 (s),1488 (m), 1382 (w), 1339 (w), 1311 (m), 1242 (s), 1136 (m), 1082(m), 1020 (s), 929 (m), 852 (m), 800 (m), 713 (m), 689 (s), 622 cm–1
(s).1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 2 H), 7.47 (dt, J =15.0, 7.2 Hz, 3 H), 7.18 (d, J = 6.1 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 2 H), 6.19(d, J = 6.6 Hz, 1 H), 4.34–4.12 (m, 2 H), 2.48 (s, 6 H), 2.25 (s, 3 H), 1.22(t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.9, 166.6, 137.8, 137.1, 134.1,131.8, 131.0, 130.2, 128.7, 127.2, 62.2, 52.8, 21.0, 20.5, 14.2.MS (ESI): m/z [M + H]+ calcd for C20H24NO3: 326.2; found: 326.1.HRMS (MALDI): m/z [M + H]+ calcd for C20H24NO3: 326.1751; found:326.1751.
Ethyl 2-Benzamido-2-(4-methoxyphenyl)acetate (4c)Bi Catalysis: Compound 4c was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), anisole (0.32 mL, 3.0 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (4.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid(236 mg, 75%; r.r. = 75:25).Fe Catalysis: Compound 4c was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), anisole (0.16 mL, 1.5 mmol, 3.0 equiv), andFe(ClO4)3 (9 mg, 0.050 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorlesssolid (105 mg, 67%; r.r. = 75:25). Further purification of the major re-gioisomer could be achieved by precipitation from hexane/CH2Cl2(r.r. = 78:22, as judged by 1H NMR analysis). Analytical data were ob-tained for this purified mixture.Mp 65.6 °C; Rf = 0.49 (cyclohexane/EtOAc = 7:3).IR (ATR): 3319 (w), 2964 (w), 1737 (s), 1633 (s), 1578 (w), 1530 (m),1512 (s), 1490 (m), 1462 (w), 1366 (w), 1317 (m), 1248 (s), 1022 (m),801 (m), 762 (m), 692 cm–1 (s).1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.78–7.72 (m, 2H), 7.47–7.28 (m, 5 H), 7.03 (d, J = 6.6 Hz, 1 H), 6.85–6.79 (m, 2 H),5.63 (d, J = 7.0 Hz, 1 H), 4.24–4.07 (m, 2 H), 3.72 (s, 3 H), 1.20–1.14 (m,3 H).13C NMR (101 MHz, CDCl3): δ = 171.3, 166.5, 159.7, 133.8, 131.8,131.6, 130.8, 129.8, 128.9, 128.7, 128.5 128.4, 127.1, 121.1, 114.4,111.1, 62.0, 61.6, 56.3, 55.6, 55.3, 53.9, 14.0 (peaks not assigned to re-gioisomers).MS (ESI): m/z [M + Na]+ calcd for C18H19NO4Na: 336.1; found: 336.4.HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO4 314.1387, found314.1384.
Ethyl 2-Benzamido-2-(4-methoxy-3-methylphenyl)acetate (4d)Bi Catalysis: Compound 4d was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 1-methoxy-2-methylbenzene (0.19 mL,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 5 mol%) in
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MeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (115 mg, 70%; r.r. = >98:2).Fe Catalysis: Compound 4d was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 1-methoxy-2-methylbenzene (0.37 mL,3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) inMeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (223 mg, 68%; r.r. = 94:6). Further pu-rification of the major regioisomer could be achieved by precipitationfrom hexane/CH2Cl2 (only major regioisomer, as judged by 1H NMRanalysis). Analytical data were obtained for this purified regioisomer.Mp 95.0 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).IR (ATR): 3323 (w), 2361 (w), 1733 (s), 1635 (s), 1579 (m), 1531 (m),1508 (m), 1451 (w), 1347 (m), 1315 (m), 1278 (m), 1249 (s), 878 (m),800 (m), 751 (m), 691 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 2 H), 7.51 (t, J = 7.3Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.26 (m, 2 H), 7.06 (d, J = 6.6 Hz, 1 H),6.80 (d, J = 8.4 Hz, 1 H), 5.66 (d, J = 7.0 Hz, 1 H), 4.34–4.13 (m, 2 H),3.82 (s, 3 H), 2.21 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.5, 166.6, 158.1, 134.0, 131.9,129.7, 128.7, 128.4, 127.5, 127.3, 126.1, 110.3, 62.0, 56.5, 55.5, 16.4,14.2.MS (ESI): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1; found: 350.3.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:328.1543.
Ethyl 2-Benzamido-2-(4-methoxy-2-methylphenyl)acetate (4e)Bi Catalysis: Compound 4e was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 1-methoxy-3-methylbenzene (0.19 mL,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (97 mg, 59%; r.r. = 80:20).Fe Catalysis: Compound 4e was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), 1-methoxy-3-methylbenzene (0.19 mL,1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (121 mg, 63%; r.r. = 75:25). Furtherpurification of the major regioisomer could be achieved by precipita-tion from hexane/CH2Cl2 (84:16 mixture of regioisomers, as judgedby 1H NMR analysis). Analytical data were obtained for this purifiedmixture.Mp 90.2 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).IR (ATR): 3343 (w), 2937 (w), 1732 (s), 1638 (s), 1611 (m), 1579 (m),1486 (m), 1347 (m), 1293 (m), 1252 (s), 1111 (m), 1079 (m), 925 (w),862 (m), 761 (m), 691 (s), 626 cm–1 (m).1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.89–7.73 (m, 2H), 7.55–7.38 (m, 3 H), 7.23–7.15 (m, 1 H), 7.00 (d, J = 6.5 Hz, 1 H),6.82–6.70 (m, 2 H), 5.89 (d, J = 6.9 Hz, 1 H), 4.32–4.11 (m, 2 H), 3.79 (s,3 H), 2.53 (s, 3 H), 2.35 (s, 1 H), 1.27–1.16 (m, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.8, 166.7, 159.6, 138.7, 133.9,131.9, 131.7, 130.7, 128.7, 128.6, 128.6, 127.8, 127.7, 127.3, 127.3,121.8, 116.6, 112.2, 111.9, 62.0, 55.7, 55.4, 53.3, 21.8, 19.9, 14.2(peaks not assigned to regioisomers).
MS (ESI): m/z [M + H]+ calcd for C19H22NO4: 328.2; found: 328.3.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:328.1543.
Ethyl 2-Benzamido-2-(2-methoxy-5-methylphenyl)acetate (4f)Bi Catalysis: Compound 4f was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 1-methoxy-4-methylbenzene (0.19 mL,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (102 mg, 62%; r.r. = >98:2).Fe Catalysis: Compound 4f was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 1-methoxy-4-methylbenzene (0.38 mL,3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) inMeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (205 mg, 63%; r.r. = >98:2).Mp 100.3 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).IR (ATR): 3263 (m), 2908 (w), 2832 (w), 1732 (s), 1637 (s), 1579 (w),1524 (m), 1506 (m), 1461 (m), 1390 (w), 1365 (m), 1323 (s), 1254 (s),1206 (s), 1135 (s), 1091 (s), 1033 (s), 978 (w), 874 (m), 805 (s), 761(m), 717 (s), 690 (s), 604 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.52–7.46 (m, 1 H),7.42 (t, J = 7.4 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.25 (d, J = 1.9 Hz, 1 H),7.10 (dd, J = 8.3, 1.7 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 5.89 (d, J = 8.3 Hz,1 H), 4.25–4.16 (m, 2 H), 3.83 (s, 3 H), 2.30 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDCl3): δ = 171.3, 166.7, 155.1, 134.4, 131.7,131.6, 130.6, 130.2, 128.6, 127.3, 125.5, 111.2, 61.7, 55.8, 54.1, 20.6,14.3.MS (ESI): m/z [M + Na]+ calcd for C19H21NO4Na: 350.1; found: 350.2.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:328.1543.
Ethyl 2-Benzamido-2-(3-chloro-4-methoxyphenyl)acetate (4g)Bi Catalysis: Compound 4g was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), 2-chloroanisole (0.38 mL, 3.0 mmol, 3.0 equiv),and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The re-action mixture was stirred for 16 h at 80 °C. Purification by chroma-tography (cyclohexane/EtOAc = 4:1) yielded the product as a colorlesssolid (266 mg, 77%; r.r. = >98:2).Fe Catalysis: Compound 4g was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 2-chloroanisole (0.38 mL, 3.0 mmol, 3.0 equiv)and FeCl3∙6H2O (14 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). Thereaction mixture was stirred for 24 h at 80 °C. Purification by chro-matography (n-hexane/EtOAc = 4:1) yielded the product as colorlesssolid (235 mg, 68%; r.r. = >98:2).Mp 89.0 °C; Rf = 0.49 (cyclohexane/EtOAc = 7:3).IR (ATR): 3310 (w), 2976 (w), 1730 (s), 1634 (s), 1604 (m), 1578 (m),1525 (s), 1489 (s), 1372 (w), 1342 (m), 1292 (s), 1255 (s), 1188 (s),1093 (s), 1063 (s), 1023 (s), 919 (w), 875 (m), 795 (m), 689 cm–1 (s).
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1H NMR (400 MHz, CDCl3): δ = 7.85–7.79 (m, 2 H), 7.55–7.41 (m, 4 H),7.33 (dd, J = 8.5, 2.2 Hz, 1 H), 7.19 (d, J = 6.6 Hz, 1 H), 6.93–6.89 (m, 1H), 5.67 (d, J = 6.8 Hz, 1 H), 4.32–4.15 (m, 2 H), 3.89 (s, 3 H), 1.25 (t, J =7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.8, 166.4, 155.1, 133.5, 131.9,130.0, 128.9, 128.7, 127.2, 127.0, 123.0, 112.2, 62.3, 56.2, 55.9, 14.03.MS (ESI): m/z [M + H]+ calcd for C18H19ClNO4: 348.1; found: 348.0.HRMS (MALDI): m/z [M + H]+ calcd for C18H19ClNO4: 348.0997; found:348.0996.
Ethyl 2-Benzamido-2-(3-bromo-4-methoxyphenyl)acetate (4h)Bi Catalysis: Compound 4h was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol), ethyl glyoxalate (122 mg, 1.2 mmol),2-bromoanisole (0.37 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg,0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixture wasstirred for 16 h at 80 °C. Purification by chromatography (n-hex-ane/EtOAc = 4:1) yielded the product as a colorless solid (344 mg,88%; r.r. = >98:2).Fe Catalysis: Compound 4h was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.30 mL,1.5 mmol, 1.5 equiv), 2-bromoanisole (0.37 mL, 3.0 mmol, 3.0 equiv),and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-action mixture was stirred for 24 h at 80 °C. Purification by chroma-tography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as acolorless solid (289 mg, 74%; r.r. = >98:2).Mp 103.7 °C; Rf = 0.51 (cyclohexane/EtOAc = 7:3).IR (ATR): 3387 (w), 2992 (w), 2942 (w), 1739 (s), 1654 (s), 1602 (w),1580 (w), 1519 (m), 1498 (m), 1484 (s), 1443 (m), 1367 (w), 1342 (w),1286 (m), 1261 (s), 1213 (s), 1179 (s), 1152 (m), 1096 (w), 1055 (m),799 (m), 713 (s), 688 (m), 665 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.85–7.80 (m, 2 H), 7.61 (d, J = 2.2 Hz, 1H), 7.52 (m, 1 H), 7.44 (dd, J = 10.2, 4.6 Hz, 2 H), 7.38 (dd, J = 8.5, 2.2Hz, 1 H), 7.18 (d, J = 6.6 Hz, 1 H), 6.90–6.86 (m, 1 H), 5.68 (d, J = 6.7 Hz,1 H), 4.32–4.16 (m, 2 H), 3.89 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.9, 166.6, 156.2, 133.7, 132.1,132.1, 130.6, 128.8, 127.9, 127.3, 112.3, 112.2, 62.4, 56.5, 55.9, 14.2.MS (ESI): m/z [M + H]+ calcd for C18H19BrNO4: 392.0; found: 392.9.HRMS (MALDI): m/z [M + H]+ calcd for C18H19BrNO4: 392.0492; found:392.0491.
Ethyl 2-Benzamido-2-(3-iodo-4-methoxyphenyl)acetate (4i)Bi Catalysis: Compound 4i was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), 2-iodoanisole (0.40 mL, 3.0 mmol, 3.0 equiv),and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The re-action mixture was stirred for 16 h at 80 °C. Purification by chroma-tography (n-hexane/EtOAc = 4:1) yielded the product as a colorlesssolid (355 mg, 81%; r.r. = >98:2).Fe Catalysis: Compound 4i was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), 2-iodoanisole (0.40 mL, 3.0 mmol, 3.0 equiv),and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorlesssolid (333 mg, 76%; r.r. = >98:2).Mp 120.6 °C; Rf = 0.54 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3390 (w), 2362 (w), 1840 (s), 1655 (s), 1600 (w), 1579 (w),1518 (m), 1483 (s), 1367 (w), 1343 (w), 1286 (m), 1259 (m), 1214 (s),1180 (s), 1153 (m), 1097 (w), 1048 (m), 1012 (s), 927 (w), 799 (m),714 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.86–7.78 (m, 3 H), 7.56–7.38 (m, 4 H),7.17 (d, J = 6.6 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 5.65 (d, J = 6.8 Hz, 1 H),4.32–4.15 (m, 2 H), 3.87 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.0, 166.6, 158.4, 138.2, 133.7,132.1, 131.1, 129.0, 128.8, 127.3, 111.1, 86.5, 62.4, 56.6, 55.7, 14.1.MS (ESI): m/z [M]+ calcd for C18H18INO4: 439.0; found: 439.2. HRMS (MALDI): m/z [M + H]+ calcd for C18H19INO4: 440.0353; found:440.0345.
Ethyl 2-Benzamido-2-(5-bromo-2-methoxyphenyl)acetate (4j)Bi Catalysis: Compound 4j was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol), ethyl glyoxalate (122 mg, 1.2 mmol),4-bromoanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3 (33 mg,0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture wasstirred for 16 h at 100 °C. Purification by chromatography (n-hex-ane/EtOAc = 4:1) yielded the product as a colorless solid (161 mg,41%; r.r. = >98:2).Fe Catalysis: Compound 4j was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol), ethyl glyoxalate (0.24 mL, 1.2 mmol),4-bromoanisole (0.38 mL, 3.0 mmol, 3.0 equiv), and Fe(ClO4)3 (18 mg,0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reaction mixture wasstirred for 16 h at 100 °C. Purification by chromatography (cyclohex-ane/EtOAc = 9:1 → 4:1) yielded the product as a colorless solid(132 mg, 34%; r.r. = >98:2).Mp 129.2 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).IR (ATR): 1738 (m), 1638 (s), 1576 (m), 1520 (m), 1486 (s), 1365 (s),1337 (m), 1315 (s), 1247 (s), 1188 (s), 1176 (s), 1131 (m), 1087 (s),1026 (s), 900 (m), 868 (m), 801 (s), 759 (w), 718 (m), 688 (s), 669 (s),653 (s), 618 (s), 590 (s), 539 (m), 500 cm–1 (w).1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.3 Hz, 2 H), 7.56 (d, J = 2.4Hz, 1 H), 7.53–7.38 (m, 4 H), 7.28–7.24 (m, 1 H), 6.82–6.75 (m, 1 H),5.88 (d, J = 8.0 Hz, 1 H), 4.27–4.17 (m, 2 H), 3.84 (s, 3 H), 1.21 (t, J = 7.1Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.7, 166.7, 156.4, 134.1, 133.5,132.5, 131.9, 128.7, 128.0, 127.3, 113.3, 113.0, 62.0, 56.1, 53.4, 14.2.MS (ESI): m/z [M + H]+ calcd for C18H19BrNO4 392.1; found: 392.1.Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57. Found: C,54.86; H, 4.50; N, 3.42.
Ethyl 2-Benzamido-2-(5-iodo-2-methoxyphenyl)acetate (4k)Bi Catalysis: Compound 4k was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), 4-iodoanisole (702 mg, 3.0 mmol, 3.0 equiv),and Bi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-action mixture was stirred for 16 h at 100 °C. Purification by chroma-tography (n-hexane/EtOAc = 4:1) yielded the product as a colorlesssolid (261 mg, 59%; r.r. = >98:2).Fe Catalysis: Compound 4k was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 4-iodoanisole (702 mg, 3.0 mmol, 3.0 equiv),and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-action mixture was stirred for 24 h at 80 °C. Purification by chroma-tography (cyclohexane/EtOAc = 4:1) yielded the product as a colorlesssolid (221 mg, 50%; r.r. = >98:2).
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Mp 102.4 °C; Rf = 0.46 (cyclohexane/EtOAc = 7:3).IR (ATR): 3277 (w), 3054 (w), 2933 (w), 2835 (w), 1739 (s), 1637 (s),1602 (w), 1578 (w), 1523 (m), 1486 (s), 1456 (m), 1391 (w), 1366 (w),1336 (m), 1317 (m), 1294 (m), 1247 (s), 1188 (s), 1134 (m), 1093 (m),1025 (s), 800 (m), 689 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.83–7.75 (m, J = 13.0, 7.6 Hz, 2 H),7.75–7.68 (m, 1 H), 7.63–7.37 (m, 4 H), 7.31–7.20 (m, 1 H), 6.71–6.64(m, 1 H), 5.86 (d, J = 8.0 Hz, 1 H), 4.26–4.15 (m, 2 H), 3.82 (s, 3 H), 1.21(t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.7, 166.7, 157.2, 139.2, 138.6,134.1, 131.9, 128.7, 128.4, 127.3, 113.5, 83.2, 62.0, 55.9, 53.3, 14.3.MS (ESI): m/z [M + Na]+ calcd for C18H18INO4Na: 462.0; found: 462.2.HRMS (MALDI): m/z [M + H]+ calcd for C18H19INO4: 440.0353; found:440.0347.
Ethyl 2-Benzamido-2-(2,5-dimethylphenyl)acetate (4l)Bi Catalysis: Compound 4l was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), p-xylene (0.19 mL, 1.5 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil(62 mg, 40%).Fe Catalysis: Compound 4l was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), p-xylene (0.19 mL, 1.5 mmol, 3.0 equiv), andFe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil(53 mg, 32%); Rf = 0.38 (cyclohexane/EtOAc = 7:3).IR (ATR): 3338 (w), 2977 (w), 2925 (w), 2869 (w), 1737 (s), 1638 (s),1578 (w), 1531 (s), 1489 (m), 1366 (w), 1344 (s), 1285 (m), 1219 (m),1198 (s), 1077 (w), 1021 (m), 808 (w), 689 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 2 H), 7.55–7.41 (m, 3H), 7.13–7.01 (m, 4 H), 5.93 (d, J = 7.0 Hz, 1 H), 4.35–4.11 (m, 2 H),2.51 (s, 3 H), 2.30 (s, 3 H), 1.29–1.19 (m, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.6, 166.5, 136.1, 135.0, 133.8,133.7, 131.8, 130.9, 129.2, 128.6, 127.2, 127.0, 61.9, 53.6, 21.0, 19.1,14.0.MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found312.1595.
Ethyl 2-Benzamido-2-(3-methyl-5-pivalamidophenyl)acetate (4m)Bi Catalysis: Compound 4m was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), 3-methylpivalanilide (287 mg,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.Purification by chromatography (n-hexane/EtOAc 4:1) yielded theproduct as a yellow solid (13 mg, 67%; r.r. = >98:2).Fe Catalysis: Compound 4m was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.0 equiv), 3-methylpivalanilide (287 mg,1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.Purification by chromatography (n-hexane/EtOAc = 4:1) yielded theproduct as a yellow solid (158 mg, 80%; r.r. = 71:29).
Mp 157–159 °C; Rf = 0.5 (n-hexane/EtOAc = 1:1).IR (ATR): 3244 (w), 2962 (w), 1742 (s), 1666 (m), 1638 (s), 1600 (m),1582 (w), 1524 (s), 1505 (s), 1481 (m), 1443 (m), 1399 (m), 1387 (m),1369 (m), 1335 (s), 1252 (m), 1194 (s), 1158 (s), 1105 (m), 1076 (m),1019 (m), 949 (w), 911 (m), 872 (m), 839 (w), 829 (w), 814 (w), 796(w), 769 (m), 691 (s), 665 (m), 596 (m), 567 (w), 519 (w), 489 cm–1
(w).1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.80–7.78 (m, 2H), 7.52–7.48 (m, 1 H), 7.44–7.37 (m, 4 H), 7.31 (br s, 1 H), 7.23 (d, J =8.2 Hz, 1 H), 7.08 (br d, J = 6.7 Hz, 1 H), 5.90 (d, J = 6.9 Hz, 1 H), 4.27–4.12 (m, 2 H), 2.53 (s, 3 H), 1.30 (s, 9 H), 1.22 (t, J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 176.8, 171.6,166.7, 138.2, 138.1, 133.8, 131.9, 131.2, 128.7, 127.2, 127.2, 122.3,118.1, 62.1, 53.4, 39.7, 27.7, 19.7, 14.1.MS (ESI): m/z [M + H]+ calcd for C23H28N2O4: 396.2; found: 419.1.HRMS (MALDI): m/z [M + H]+ calcd for C23H28N2O4: 397.2122; found:397.2182.
Ethyl 3-(1-Benzamido-2-ethoxy-2-oxoethyl)-4-methoxybenzoate (4n)Bi Catalysis: Compound 4n was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), ethyl 4-methoxybenzoate (360 mg, 2.0 mmol,4.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 72 h at 100 °C. Purifica-tion by chromatography (n-hexane/EtOAc = 4:1) yielded the productas a yellow oil (77 mg, 40%; r.r. = >98:2).Fe Catalysis: Compound 4n was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.0 equiv), ethyl 4-methoxybenzoate (270 mg, 1.5 mmol,3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 100 °C. Purifica-tion by chromatography (n-hexane/EtOAc = 4:1) yielded the productas a yellow oil (128 mg, 66%; r.r. = 71:28); Rf = 0.3 (hexane/EtOAc =7:3).IR (ATR): 3342 (w), 2981 (w), 2843 (w), 1741 (m), 1711 (s), 1650 (s),1608 (m), 1580 (m), 1506 (m), 1484 (m), 1465 (m), 1445 (m), 1391(w), 1368 (m), 1322 (m), 1297 (m), 1265 (s), 1238 (s), 1204 (s), 1188(s), 1130 (s), 1103 (m), 1023 (s), 913 (m), 862 (m), 831 (m), 801 (m),771 (m), 713 (s), 692 (m), 647 (m), 630 (m), 589 (m), 541 (m), 473cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 2.1 Hz, 1 H), 8.04 (dd, J = 8.6,2.2 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.53–7.43 (m, 3 H), 7.27 (br s, 1 H),6.93 (d, J = 8.7 Hz, 1 H), 6.00 (d, J = 8.0 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H),4.20 (q, J = 7.1 Hz, 2 H), 3.92 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.20 (t, J =7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 170.86, 166.73, 166.11, 160.76, 134.16,132.20, 132.13, 131.84, 128.69, 127.31, 125.93, 123.56, 110.71, 61.98,61.01, 56.06, 53.61, 14.53, 14.23.MS (ESI): m/z [M + Na]+ calcd for C21H23NO6Na: 408.1; found: 408.1.HRMS (MALDI): m/z [M + H]+ calcd for C21H24NO6 386.1598; found:386.1600.
Ethyl 2-Benzamido-2-(3,4,5-trimethoxyphenyl)acetate (4o)Bi Catalysis: Compound 4o was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 1,2,3-trimethoxybenzene (253 mg, 3.0 mmol,3.0 equiv), Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%), and in MeNO2
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(2.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 7:3) yielded theproduct as a colorless oil (127 mg, 68%; r.r. = >98:2).Fe Catalysis: Compound 4o was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 1,2,3-trimethoxybenzene (505 mg, 3.0 mmol,3.0 equiv), Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%), and 2,2′-bipyridine(0.06 mmol, 6 mol%, 9 mg) in MeNO2 (4.0 mL). The reaction mixturewas stirred for 24 h at 100 °C. Purification by chromatography (cyclo-hexane/EtOAc = 9:1 → 7:3) yielded the product as a colorless oil(216 mg, 58%; r.r. = >98:2); Rf = 0.23 (cyclohexane/EtOAc = 7:3).IR (ATR): 3347 (w), 2979 (w), 2939 (w), 2837 (w), 1721 (m), 1670 (m),1600 (m), 1581 (m), 1516 (m), 1494 (s), 1465 (w), 1418 (m), 1369(m), 1313 (m), 1278 (s), 1244 (s), 1203 (s), 1172 (s), 1092 (s), 1055 (s),1015 (s), 964 (m), 909 (m), 873 (m), 798 (m), 746 (m), 713 (m), 692(m), 667 (m), 570 (m), 514 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.83–7.79 (m, 2 H), 7.52–7.47 (m, 1 H),7.45–7.40 (m, 2 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.12 (d, J = 8.6 Hz, 1 H),6.67–6.64 (m, 1 H), 5.86 (d, J = 7.9 Hz, 1 H), 4.31–4.15 (m, 2 H), 3.95 (s,3 H), 3.86 (s, 3 H), 3.86 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.5, 166.7, 154.3, 151.8, 142.2,134.3, 131.8, 128.7, 127.3, 124.6, 123.5, 107.3, 61.9, 61.1, 60.9, 56.1,53.6, 14.3.MS (ESI): m/z [M + Na]+ calcd for C20H23NO6Na: 396.1; found: 396.3.HRMS (MALDI): m/z [M + H]+ calcd for C21H24NO6: 374.1598; found:374.15988.
Ethyl 2-Benzamido-2-(4-methoxy-2,6-dimethylphenyl)acetate (4p)Bi Catalysis: Compound 4p was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6mmol, 1.2 equiv), 1-methoxy-3,5-dimethylbenzene (204 mg,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (n-hexane/EtOAc = 9:1 → 4:1) yieldedthe product as a colorless oil (84 mg, 50%; r.r. = 67:33).Fe Catalysis: Compound 4p was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), 1-methoxy-3,5-dimethylbenzene (204 mg,1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.Purification by chromatography (cyclohexane/EtOAc = 9:1 → 4:1)yielded the product as a yellowish oil (106 mg, 62%; r.r. = 50:50); Rf =0.57 (cyclohexane/EtOAc = 7:3).IR (ATR): 3449 (w), 3319 (s), 2977 (m), 2840 (w), 2099 (s), 1739 (s),1655 (s), 1651 (s), 1624 (m), 1599 (m), 1580 (m), 1512 (s), 1482 (s),1446 (m), 1367 (m), 1318 (s), 1251 (s), 1207 (s), 1186 (s), 1147 (s),1094 (s), 1024 (s), 1002 (m), 973 (m), 931 (m), 906 (m), 887 (m), 862(m), 848 (m), 810 (s), 745 (m), 709 (s), 691 (s), 672 (m), 645 (m), 608(m), 590 (m), 546 (m), 526 (m), 502 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.50–7.39 (m, 3 H),7.17 (d, J = 6.1 Hz, 1 H), 6.75–6.44 (m, 2 H), 6.23–6.12 (m, 1 H), 4.32–4.10 (m, 2 H), 3.85–3.74 (m, 3 H), 2.56 (s, 2 H), 2.49 (s, 2 H), 2.31 (s, 2H), 1.28–1.15 (m, 3 H) (peaks not assigned to regioisomers).13C NMR (101 MHz, CDCl3): δ = 171.9, 171.5, 166.6, 166.4, 158.7,157.5, 139.0, 138.3, 134.5, 133.9, 131.7, 131.5, 128.6, 128.5, 127.2,127.1, 126.3, 124.2, 122.2, 114.4, 109.7, 62.0, 61.4, 55.5, 55.0, 52.5,50.2, 21.5, 20.8, 19.9, 14.2, 14.1 (peaks not assigned to regioisomers).
MS (ESI): m/z [M + H]+ calcd for C20H24NO4: 342.1; found: 342.2.HRMS (MALDI): m/z [M + H]+ calcd for C20H24NO4: 342.1053; found:342.1696.
Ethyl 2-Benzamido-2-(2-methoxynaphthalen-1-yl)acetate (4q)Bi Catalysis: Compound 4q was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6mmol, 1.2 equiv), 2-methoxynaphthalene (237 mg, 1.5 mmol, 3.0equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (n-hexane/EtOAc = 4:1) yielded the product as an or-ange oil (89 mg, 49%).Fe Catalysis: Compound 4q was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), 2-methoxynaphthalene (237 mg, 1.5 mmol, 3.0equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 24 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-uct as an orange oil (123 mg, 64%); Rf = 0.31 (cyclohexane/EtOAc =7:3).IR (ATR): 3446 (w), 2979 (w), 2841 (w), 2099 (w), 1739 (s), 1651 (s),1626 (m), 1598 (m), 1580 (m), 1560 (m), 1512 (s), 1482 (s), 1473 (s),1445 (m), 1386 (s), 1367 (m), 1319 (m), 1267 (s), 1251 (s), 1204 (s),1185 (s), 1147 (s), 1086 (s), 1024 (s), 906 (m), 888 (w), 864 (m), 848(m), 810 (s), 783 (m), 709 (s), 692 (s), 672 (m), 645 (m), 605 (m), 589(m), 546 (m), 526 (m), 502 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.7 Hz, 1 H), 7.88 (d, J = 9.0Hz, 1 H), 7.84–7.78 (m, 3 H), 7.62–7.57 (m, 1 H), 7.50–7.36 (m, 5 H),7.30 (d, J = 9.0 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 4.23–4.16 (m, 2 H),3.99 (s, 3 H), 1.16 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.8, 167.0, 155.3, 134.4, 132.6,131.7, 130.8, 129.6, 128.7, 128.6, 127.8, 127.4, 124.1, 123.1, 119.5,113.1, 61.7, 56.6, 49.0, 14.3.MS (ESI): m/z [M + H]+ calcd for C22H22NO4: 364.2; found: 364.3.HRMS (MALDI): m/z [M + H]+ calcd for C22H22NO4: 364.1543; found:364.1544.
Ethyl 2-Benzamido-2-(pyren-4-yl)acetate (4r)Bi Catalysis: Compound 4r was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), pyrene (303 mg, 1.5 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(n-hexane/EtOAc = 4:1) yielded the product as a colorless solid(111 mg, 54%; r.r. = >98:2).Fe Catalysis: Compound 4r was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), pyrene (303 mg, 1.5 mmol, 3.0 equiv), andFe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 24 h at 80 °C. Purification by chromatography(cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded the product as a col-orless solid (115 mg, 57%; r.r. = >98:2).Mp 207.3 °C; Rf = 0.48 (cyclohexane/EtOAc = 7:3).IR (ATR): 3331 (w), 2985 (w), 2360 (w), 2342 (w), 1740 (s), 1635 (s),1602 (w), 1579 (w), 1517 (w), 1489 (m), 1374 (w), 1349 (m), 1313(w), 1204 (s), 1183 (m), 1150 (m), 1089 (m), 1021 (m), 845 (s), 824(m), 692 cm–1 (s).
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1H NMR (400 MHz, CDCl3): δ = 8.61–8.54 (m, 1 H), 8.25–8.01 (m, 8 H),7.86–7.79 (m, 2 H), 7.49 (dd, J = 14.0, 6.6 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2H), 7.26 (s, 1 H), 6.83 (d, J = 7.3 Hz, 1 H), 4.36–4.15 (m, 2 H), 1.18 (t, J =7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.8, 166.9, 133.8, 132.0, 131.8,131.4, 130.9, 130.1, 129.3, 128.9, 128.7, 128.2, 127.4, 127.3, 126.4,125.8, 125.7, 125.4, 125.2, 125.1, 124.8, 122.8, 62.3, 54.3, 14.2.MS (ESI): m/z [M]+ calcd for C27H21NO3: 407.2; found: 407.2.HRMS (MALDI): m/z [M]+ calcd for C27H21NO3: 407.1516; found:407.1513.
Ethyl 2-Mesityl-2-(4-methoxybenzamido)acetate (5a)Bi Catalysis: Compound 5a was synthesized according to the GP from4-methoxybenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 4:1) yielded the product as acolorless solid (145 mg, 81%).Fe Catalysis: Compound 5a was synthesized according to the GP from4-methoxybenzamide (73 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded theproduct as a colorless solid (166 mg, 94%).Mp 109.8 °C; Rf = 0.36 (cyclohexane/EtOAc = 7:3).IR (ATR): 3432 (w), 2921 (m), 2851 (m), 1726 (m), 1652 (s), 1605 (m),1524 (w), 1486 (s), 1366 (m), 1349 (m), 1306 (m), 1252 (s), 1214 (w),1193 (s), 1175 (s), 1088 (m), 1021 (s), 845 (m), 767 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.7 Hz, 2 H), 7.08 (d, J = 6.3Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 6.85 (s, 2 H), 6.18 (d, J = 6.5 Hz, 1 H),4.32–4.11 (m, 2 H), 3.84 (s, 3 H), 2.47 (s, 6 H), 2.25 (s, 3 H), 1.22 (t, J =7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 172.1, 166.1, 162.5, 137.7, 137.1,131.1, 130.1, 129.0, 126.3, 113.9, 62.1, 55.5, 52.8, 21.0, 20.5, 14.2.MS (ESI): m/z [M + H]+ calcd for C21H26NO4 356.2; found: 356.2.HRMS (MALDI): m/z [M + H]+ calcd for C21H26NO4 356.1856; found:356.1856.
Ethyl 2-(4-Bromobenzamido)-2-mesitylacetate (5b)Bi Catalysis: Compound 5b was synthesized according to the GP from4-bromobenzamide (100 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 4:1) yielded the product as acolorless solid (161 mg, 80%).Fe Catalysis: Compound 5b was synthesized according to the GP from4-bromobenzamide (100 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a colorless solid (172 mg, 85%).Mp 89.5 °C; Rf = 0.70 (cyclohexane/EtOAc = 7:3).
IR (ATR): 3427 (w), 2969 (w), 1731 (s), 1660 (s), 1607 (w), 1588 (m),1566 (w), 1506 (s), 1473 (s), 1366 (m), 1352 (w), 1309 (s), 1256 (m),1212 (w), 1189 (s), 1159 (m), 881 (m), 848 (m), 777 (m), 751 (s), 613cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.71–7.51 (m, 4 H), 7.14 (d, J = 6.2 Hz, 1H), 6.86 (s, 2 H), 6.15 (d, J = 6.5 Hz, 1 H), 4.33–4.12 (m, 2 H), 2.46 (s, 6H), 2.25 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.8, 165.6, 137.9, 137.1, 132.89,132.0, 130.8, 130.2, 128.8, 126.6, 62.3, 52.9, 21.0, 20.5, 14.2.MS (ESI): m/z [M + Na]+ calcd for C20H22BrNO3Na: 428.1; found 428.2.HRMS (MALDI): m/z [M + H]+ calcd for C20H23BrNO3: 404.0856; found:404.0854.
Ethyl 2-Mesityl-2-(4-nitrobenzamido)acetate (5c)Bi Catalysis: Compound 5c was synthesized according to the GP from4-nitrobenzamide (83 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 4:1) yielded the product as acolorless solid (125 mg, 68%).Fe Catalysis: Compound 5c was synthesized according to the GP from4-nitrobenzamide (166 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,3.0 equiv), and FeCl3·6H2O (14 mg, 0.050 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a colorless solid (329 mg, 89%).Mp 119.2 °C; Rf = 0.36 (cyclohexane/EtOAc = 7:3).IR (ATR): 3349 (w), 2978 (w), 1731 (s), 1634 (m), 1598 (m), 1525 (s),1488 (m), 1460 (w), 1343 (m), 1297 (m), 1240 (s), 1148 (w), 1077(m), 1024 (m), 928 (w), 876 (m), 853 (m), 799 (m), 761 (w), 720 (s),679 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 8.7 Hz, 2 H), 7.95 (d, J = 8.7Hz, 2 H), 7.27–7.22 (m, 1 H), 6.87 (s, 2 H), 6.15 (d, J = 6.4 Hz, 1 H),4.34–4.12 (m, 2 H), 2.46 (s, 6 H), 2.26 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.6, 164.6, 149.9, 139.6, 138.2,137.1, 130.4, 130.3, 128.4, 124.0, 62.5, 53.1, 21.0, 20.5, 14.2.MS (ESI): m/z [M + Na]+ calcd for C20H22N2O5Na: 393.1; found: 393.3.HRMS (MALDI): m/z [M + Na]+ calcd for C20H22N2O5Na: 393.1421;found: 393.1421.
Ethyl 2-(2-Chloroacetamido)-2-mesitylacetate (5d)Bi Catalysis: Compound 5d was synthesized according to the GP from2-chloroacetamide (47 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). Thereaction mixture was stirred for 16 h at 80 °C. Purification by chro-matography (cyclohexane/EtOAc = 4:1 → 7:3) yielded the product as acolorless oil (121 mg, 81%).Fe Catalysis: Compound 5d was synthesized according to the GP from2-chloroacetamide (47 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and FeCl3·6H2O (3 mg, 0.010 mmol, 2 mol%) in MeNO2 (2.0mL). The reaction mixture was stirred for 24 h at 80 °C. Purificationby chromatography (cyclohexane/EtOAc = 4:1 → 7:3) yielded theproduct as a colorless oil (131 mg, 88%); Rf = 0.30 = (cyclohexane/EtOAc = 7:3).
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IR (ATR): 3307 (w), 2975 (w), 1733 (s), 1660 (m), 1519 (m), 1463 (w),1370 (w), 1311 (m), 1195 (s), 1150 (m), 1096 (m), 1017 (s), 925 (w),853 (m), 769 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 6.2 Hz, 1 H), 6.87–6.82 (m, 2H), 5.99 (d, J = 7.2 Hz, 1 H), 4.32–3.97 (m, 4 H), 2.40 (s, 6 H), 2.25 (s, 3H), 1.21 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.1, 165.3, 138.4, 137.1, 130.4,130.2, 129.9, 69.3, 62.2, 52.5, 42.7, 21.0, 20.4, 20.1, 14.2.MS (ESI): m/z [M + Na]+ calcd for C15H20ClNO3Na: 320.1; found: 320.2.HRMS (MALDI): m/z [M + H]+ calcd for C15H21ClNO3: 298.1205; found:298.1202.
Ethyl 2-Acetamido-2-mesitylacetate (5e)Bi Catalysis: Compound 5e was synthesized according to the GP fromacetamide (59 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), andBi(OTf)3 (33 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a colorlesssolid (209 mg, 79%).Fe Catalysis: Compound 5e was synthesized according to the GP fromacetamide (30 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), andFeCl3·6H2O (7 mg, 0.020 mmol, 2 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1 → 1:1) yielded the product as a color-less solid (93 mg, 70%).Mp 95.8 °C; Rf = 0.29 (cyclohexane/EtOAc = 1:1).IR (ATR): 3302 (m), 2976 (w), 2360 (w), 1748 (s), 1649 (s), 1524 (s),1366 (m), 1310 (w), 1281 (w), 1211 (s), 1192 (s), 1149 (m), 1124 (m),1022 (m), 855 (m), 832 (w), 797 (w), 644 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 6.40 (d, J = 6.4 Hz, 1 H),6.02 (d, J = 7.2 Hz, 1 H), 4.28–4.07 (m, 2 H), 2.38 (s, 6 H), 2.25 (s, 3 H),2.01 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.9, 169.4, 137.8, 137.0, 131.2,130.1, 62.0, 52.2, 23.2, 21.0, 20.4, 14.2.MS (ESI): m/z [M + Na]+ calcd for C15H21NO3Na: 286.1; found: 286.2.HRMS (MALDI): m/z [M + H]+ calcd for C15H22NO3: 264.1594; found:264.1597.
Ethyl 2-Mesityl-2-pivalamidoacetate (5f)Bi Catalysis: Compound 5f was synthesized according to the GP frompivalamide (100 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (4.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil(248 mg, 81%).Fe Catalysis: Compound 5f was synthesized according to the GP frompivalamide (50 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv) andFeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 4:1) yielded the product as a colorless oil(122 mg, 80%); Rf = 0.44 (cyclohexane/EtOAc = 7:3).IR (ATR): 3448 (w), 2961 (m), 1731 (s), 1670 (s), 1611 (w), 1494 (s),1395 (w), 1366 (m), 1308 (m), 1257 (m), 1185 (s), 1100 (m), 1016(m), 907 (w), 852 (m), 770 cm–1 (w).
1H NMR (300 MHz, CDCl3): δ = 6.83 (s, 2 H), 6.68 (d, J = 6.0 Hz, 1 H),5.96 (d, J = 6.7 Hz, 1 H), 4.30–4.06 (m, 2 H), 2.40 (s, 6 H), 2.24 (s, 3 H),1.24–1.16 (m, 12 H).13C NMR (101 MHz, CDCl3): δ = 177.7, 172.0, 137.60, 137.0, 131.1,130.1, 62.0, 52.4, 38.9, 27.7, 21.0, 20.4, 14.2.MS (ESI): m/z [M + H]+ calcd for C18H28NO3: 306.2; found: 306.2.HRMS (MALDI): m/z [M + H]+ calcd for C18H28NO3: 306.2064; found:306.2064.
Ethyl 2-Acrylamido-2-mesitylacetate (5g)Bi Catalysis: Compound 5g was synthesized according to the GP fromacrylamide (71 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg,1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 1 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 16 h at 80 °C. Purification by chromatography(cyclohexane/EtOAc = 4:1) yielded the product as a colorless solid(226 mg, 82%).Fe Catalysis: Compound 5g was synthesized according to the GP fromacrylamide (71 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol, 3.0 equiv), andFeCl3·6H2O (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 7:3) yielded the product as a colorlesssolid (233 mg, 85%).Mp 117.2 °C; Rf = 0.43 (cyclohexane/EtOAc = 7:3).IR (ATR): 3304.43 (s), 2983 (s), 1748 (s), 1652 (m), 1614 (m), 1519 (s),1404 (m), 1368 (s), 1311 (s), 1209 (m), 1187 (s), 1148 (m), 1113 (m),1072 (s), 1023 (m), 990 (m), 958 (s), 856 (m), 810 (m), 604 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 6.59 (t, J = 16.2 Hz, 1 H),6.29 (dd, J = 16.9, 1.0 Hz, 1 H), 6.16 (dd, J = 17.0, 10.1 Hz, 1 H), 6.07 (d,J = 6.9 Hz, 1 H), 5.66 (dd, J = 10.1, 1.0 Hz, 1 H), 4.30–4.09 (m, 2 H), 2.40(s, 6 H), 2.24 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.8, 164.7, 137.8, 137.1, 130.9,130.4, 130.1, 127.4, 62.1, 52.4, 21.0, 20.4, 14.2.MS (ESI): m/z [M + H]+ calcd for C16H22NO3: 276.2; found: 276.2.HRMS (MALDI): m/z [M + H]+ calcd for C16H22NO3: 276.1594; found:276.1595.
Ethyl 2-[(Ethoxycarbonyl)amino]-2-mesitylacetate (5h)Bi Catalysis: Compound 5h was synthesized according to the GP fromethyl carbamate (45 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-uct as colorless crystals (126 mg, 86%).Fe Catalysis: Compound 5h was synthesized according to the GP fromethyl carbamate (45 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a colorless solid (121 mg, 83%).Mp 54.1 °C; Rf = 0.40 (cyclohexane/EtOAc = 7:3).IR (ATR): 3374 (m), 2964 (s), 1705 (s), 1612 (w), 1509 (m), 1391 (w),1366 (m), 1308 (s), 1263 (w), 1220 (m), 1173 (w), 1091 (m), 1053 (s),947 (w), 847 (w), 781 (m), 732 (w), 694 (w), 639 cm–1 (w).
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1H NMR (500 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.83–5.71 (m, 1 H), 5.67(d, J = 6.1 Hz, 1 H), 4.16 (d, J = 91.0 Hz, 4 H), 2.37 (s, 6 H), 2.25 (s, 3 H),1.27–1.17 (m, 6 H).13C NMR (126 MHz, CDCl3): δ = 171.6, 155.8, 137.5, 136.7, 131.2,129.8, 61.7, 61.0, 53.3, 20.7, 20.0, 14.4, 14.0.MS (ESI): m/z [M + H]+ calcd for C16H24NO4: 294.2; found: 294.2.HRMS (MALDI): m/z [M + H]+ calcd for C16H24NO4: 294.1700; found:294.1700.
Ethyl 2-{[Benzyloxy)carbonyl]amino}-2-mesitylacetate (5i)Bi Catalysis: Compound 5i was synthesized according to the GP frombenzyl carbamate (76 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-uct as a colorless solid (116 mg, 65%).Fe Catalysis: Compound 5i was synthesized according to the GP frombenzyl carbamate (76 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a colorless solid (91 mg, 51%).Mp 73.5 °C; Rf = 0.38 (cyclohexane/EtOAc = 7:3).IR (ATR): 3363 (m), 2957 (s), 2360 (m), 1728 (m), 1701 (s), 1521 (s),1479 (w), 1455 (w), 1370 (w), 1306 (m), 1231 (s), 1048 (s), 986 (m),916 (w), 824 (m), 794 (m), 752 (s), 700 (s), 606 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.43–7.01 (m, 5 H), 6.85 (s, 2 H), 5.88–5.55 (m, 2 H), 5.17–4.99 (m, 2 H), 4.29–4.06 (m, 2 H), 2.38 (s, 6 H),2.26 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.7, 155.8, 137.8, 136.9, 136.4,131.3, 130.1, 130.1, 128.7, 128.3, 67.2, 62.0, 53.7, 21.0, 20.3, 14.2.MS (ESI): m/z [M + Na]+ calcd for C21H25NO4Na: 378.2; found: 378.3.HRMS (MALDI): m/z [M + Na]+ calcd for C21H25NO4Na: 378.1677;found: 378.1681.
Ethyl 2-{[(Allyloxy)carbonyl]amino}-2-mesitylacetate (5j)Bi Catalysis: Compound 5j was synthesized according to the GP fromallyloxycarbamate (51 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (n-hexane/EtOAc = 4:1) yielded the product as a col-orless oil (128 mg, 84%).Fe Catalysis: Compound 5j was synthesized according to the GP fromallyloxycarbamate (102 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,3.0 equiv), and FeCl3·6H2O (14 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1)yielded the product as a colorless oil (215 mg, 70%); Rf = 0.63 (cyclo-hexane/EtOAc = 7:3).IR (ATR): 3376 (w), 2981 (w), 1831 (w), 1718 (s), 1649 (w), 1611 (w),1498 (m), 1369 (m), 1305 (m), 1195 (s), 1093 (m), 1053 (s), 932 (m),852 (m), 775 cm–1 (m).
1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.98–5.68 (m, 3 H), 5.35–5.15 (m, 2 H), 4.63–4.47 (m, 2 H), 4.30–4.07 (m, 2 H), 2.37 (s, 6 H),2.25 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.8, 155.6, 137.8, 136.9, 132.8, 131.3,130.1, 118.0, 66.0, 62.0, 53.7, 21.0, 20.3, 14.2.MS (ESI): m/z [M + H]+ calcd for C17H24NO4: 306.2; found: 306.2.HRMS (MALDI): m/z [M + H]+ calcd for C17H24NO4: 306.1700; found:306.1700.
Ethyl 2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-mesityl-acetate (5k)Bi Catalysis: Compound 5k was synthesized according to the GP from(9H-fluoren-9-yl)methyl carbamate (120 mg, 0.5 mmol, 1.0 equiv),ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,3.0 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) inMeNO2 (4.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (n-hexane/EtOAc = 4:1) yielded theproduct as a colorless oil (185 mg, 83%).Fe Catalysis: Compound 5k was synthesized according to the GP from(9H-fluoren-9-yl)methyl carbamate (239 mg, 1.0 mmol, 1.0 equiv),ethyl glyoxalate (0.24 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL,3.0 mmol, 3.0 equiv), and FeCl3·6H2O (5 mg, 0.020 mmol, 2 mol%) inMeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 9:1) yieldedthe product as a colorless oil (332 mg, 75%); Rf = 0.69 (cyclohex-ane/EtOAc = 7:3).IR (ATR): 3368 (w), 2956 (w), 1718 (s), 1611 (w), 1498 (m), 1448 (m),1305 (m), 1195 (s), 1050 (s), 852 (m), 739 (s), 621 cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 2 H), 7.63–7.47 (m, 2H), 7.45–7.26 (m, 4 H), 6.86 (s, 2 H), 5.90–5.49 (m, 2 H), 4.44–4.11 (m,5 H), 2.35 (s, 6 H), 2.27 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.7, 155.7 144.1, 143.9, 141.4, 137.9,137.0, 131.1, 130.2, 127.8, 127.2, 125.2, 120.1, 67.3, 62.1, 53.8, 47.3,21.0, 20.4, 14.2.MS (ESI): m/z [M + Na]+ calcd for C28H29NO4Na: 466.2; found: 466.0.HRMS (MALDI): m/z [M + Na]+ calcd for C28H29NO4Na: 466.1989;found: 466.1993.
Ethyl 2-Benzamido-2-(5-bromothiophen-2-yl)acetate (7a)Bi Catalysis: Compound 7a was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 2-bromothiophene (0.15 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 60 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-uct as a yellow solid (102 mg, 55%; r.r. = >98:2).Fe Catalysis: Compound 7a was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 2-bromothiophene (0.29 mL, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a yellow solid (219 mg, 60%; r.r. = >98:2).Mp 95.2 °C; Rf = 0.58 (cyclohexane/EtOAc = 7:3).IR (ATR): 3309 (w), 2995 (w), 2929 (w), 1738 (s), 1636 (s), 1604 (w),1570 (w), 1525 (s), 1488 (m), 1371 (m), 1292 (s), 1205 (s), 1171 (m),1123 (w), 1083 (m), 1012 (m), 810 (m), 755 (m), 716 (s), 691 cm–1 (s).
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1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.7 Hz, 2 H), 7.57–7.51 (m, 1H), 7.49–7.43 (m, 2 H), 7.16–7.08 (m, 1 H), 6.94–6.77 (m, 2 H), 5.99–5.92 (m, 1 H), 4.37–4.23 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H) (peaks notassigned to regioisomers).13C NMR (75 MHz, CDCl3): δ = 169.6, 166.7, 140.7, 137.8, 133.4, 132.3,130.0, 128.8, 127.3, 126.6, 126.2, 125.7, 112.7, 62.8, 52.6, 14.2 (peaksnot assigned to regioisomers).MS (ESI): m/z [M + Na]+ calcd for C15H14BrNO3SNa: 390.0; found:390.1.HRMS (MALDI): m/z [M + H]+ calcd for C15H14BrNO3S: 367.9952;found: 367.9951.
Ethyl 2-(5-Bromothiophen-2-yl)-2-[(ethoxycarbonyl)amino]ace-tate (7b)Bi Catalysis: Compound 7b was synthesized according to the GP fromurethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5mmol, 1.0 equiv), 2-bromothiophene (0.16 mL, 1.5 mmol), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reactionmixture was stirred for 16 h at 60 °C. Purification by chromatography(cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid(130 mg, 77%; r.r. = >98:2).Fe Catalysis: Compound 7b was synthesized according to the GP fromurethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 2-bromothiophene (0.28 mL, 3.0 mmol), andFe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 48 h at 40 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yel-low solid (249 mg, 74%; r.r. = >98:2).Mp 48.8 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).IR (ATR): 3305 (m), 2983 (w), 2951 (w), 2904 (w), 1741 (s), 1686 (s),1526 (m), 1499 (w), 1433 (m), 1372 (m), 1312 (m), 1295 (m), 1257(m), 1216 (s), 1107 (s), 1061 (s), 1038 (s), 963 (s), 810 (w), 800 (w),780 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 3.8 Hz, 1 H), 6.82 (d, J = 3.7Hz, 1 H), 5.68 (s, 1 H), 5.53 (d, J = 7.4 Hz, 1 H), 4.31–4.20 (m, 2 H),4.19–4.11 (m, 2 H), 1.31–1.23 (m, 6 H).13C NMR (101 MHz, CDCl3): δ = 169.5, 155.6, 141.1, 129.9, 126.3,112.6, 62.6, 61.7, 53.8, 14.6, 14.2.MS (ESI): m/z [M + Na]+ calcd for C11H14BrNO4SNa: 358.0; found:358.1.HRMS (MALDI): m/z [M + K]+ calcd for C11H14BrNO4SK: 373.9464;found: 373.9453.
Ethyl 2-Benzamido-2-(5-chlorothiophen-2-yl)acetate (7c)Bi Catalysis: Compound 7c was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 2-chlorothiophene (0.15 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 60 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the prod-uct as a yellow solid (119 mg, 37%; r.r. = >98:2).Fe Catalysis: Compound 7c was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 2-chlorothiophene (0.28 mL, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a yellow low-melting solid (161 mg, 50%; r.r. = 63:37).
Rf = 0.58 (cyclohexane/EtOAc = 7:3).IR (ATR): 3300 (w), 2978 (w), 2929 (w), 1983 (w), 1983 (w), 1739 (s),1635 (s), 1604 (w), 1579 (w), 1525 (s), 1587 (m), 1443 (m), 1369 (m),1324 (m), 1290 (s), 1204 (s), 1166 (m), 1125 (m), 1086 (m), 1021 (m),989 (m), 881 (m), 810 (m), 754 (m), 715 (s), 690 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.6 Hz, 2 H), 7.57–7.42 (m, 3H), 7.12 (d, J = 6.3 Hz, 1 H), 6.95–6.76 (m, 2 H), 5.99–5.91 (m, 1 H),4.37–4.23 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 169.7, 166.7, 140.7, 137.8, 133.4,132.3, 130.5, 130.0, 128.9, 127.3, 126.6, 126.2, 125.7, 62.8, 52.6, 52.6,14.2 (peaks not assigned to regioisomers).MS (ESI): m/z [M + Na]+ calcd for C15H14ClNO3SNa: 346.0; found:346.2.HRMS (MALDI): m/z [M + H]+ calcd for C15H15ClNO3S: 324.0456;found: 324.0454.
Ethyl 2-(5-Chlorothiophen-2-yl)-2-[(ethoxycarbonyl)amino]ace-tate (7d)Bi Catalysis: Compound 7d was synthesized according to the GP fromurethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg, 0.5mmol, 1.0 equiv), 2-chlorothiophene (0.16 mL, 1.5 mmol), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL). The reactionmixture was stirred for 16 h at 60 °C. Purification by chromatography(cyclohexane/EtOAc 9:1 → 4:1) yielded the product as a yellow solid(76 mg, 52%; r.r. = >98:2).Fe Catalysis: Compound 7d was synthesized according to the GP fromurethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), 2-chlorothiophene (0.29 mL, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 48 h at 40 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a yellow solid (219 mg, 75%; r.r. = >98:2).Mp 46.9 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).IR (ATR): 3310 (m), 2985 (w) 1741 (s), 1686 (s), 1528 (m), 1443 (m),1371 (m), 1355 (m), 1206 (s), 1045 (s), 986 (s), 964 (w), 869 (w), 780(m), 664 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 6.84–6.82 (m, 1 H), 6.77 (d, J = 3.8 Hz, 1H), 5.68 (s, 1 H), 5.51 (d, J = 7.3 Hz, 1 H), 4.31–4.10 (m, 4 H), 1.34–1.14(m, 6 H).13C NMR (75 MHz, CDCl3): δ = 169.5 155.6, 138.2, 130.4, 126.2, 125.4,62.6, 61.7, 53.9, 14.6, 14.1.MS (ESI): m/z [M + Na]+ calcd for C11H14ClNO4SNa: 314.0; found:314.2.HRMS (MALDI): m/z [M + K]+ calcd for C11H14ClNO4SK: 329.9964;found: 329.9970.
Ethyl 2-Benzamido-2-(5-methylthiophen-2-yl)acetate (7e)Bi Catalysis: Compound 7e was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (1.0 mL).The reaction mixture was stirred for 16 h at r.t. Purification by chro-matography (cyclohexane/EtOAc = 4:1) yielded the product as a color-less solid (97 mg, 64%; r.r. = 89:11). Fe Catalysis: Compound 7e was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol,3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2
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(2.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-uct as a yellow solid (72 mg, 47%; r.r. = 88:12).Mp 66–68 °C; Rf = 0.3 (cyclohexane/EtOAc = 4:1).IR (ATR): 3315 (w), 2981 (w), 2917 (w), 1737 (s), 1637 (s), 1603 (m),1579 (m), 1523 (s), 1486 (s), 1446 (m), 1369 (m), 1327 (m), 1294 (m),1229 (m), 1204 (s), 1172 (s), 1122 (m), 1083 (m), 1019 (s), 976 (m),929 (w), 883 (w), 803 (m), 754 (m), 714 (s), 691 (s), 672 (s), 622 (m),601 (s), 579 (s), 557 (s), 537 (s), 522 (s), 505 (m), 480 (m), 472 cm–1
(m).1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 7.83–7.79 (m, 2H), 7.54–7.41 (m, 3 H), 7.05 (br d, J = 5.5 Hz, 1 H), 6.92–6.89 (m, 1 H),6.64–6.60 (m, 1 H), 5.95 (d, J = 7.4 Hz, 1 H), 4.36–4.18 (m, 2 H), 2.44 (s,3 H), 1.32–1.22 (m, 3 H).13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 171.21, 170.29,166.66, 140.68, 136.33, 133.80, 133.68, 132.04, 131.94, 128.73,127.32, 127.25, 126.37, 125.81, 125.26, 122.71, 62.39, 62.09, 52.63,50.95, 15.43, 14.17, 13.25.MS (ESI): m/z [M + H]+ calcd for C16H18NO3: 303.1; found: 304.3.HRMS (MALDI): m/z [M + Na]+ calcd for C16H17NO3SNa: 326.0821;found: 326.0821.
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(5-methylthiophen-2-yl)ace-tate (7f)Bi Catalysis: Compound 7f was synthesized according to the GP fromurethane (67 mg, 0.75 mmol, 1.5 equiv), ethyl glyoxalate (51 mg,0.5 mmol, 1.0 equiv), 2-methylthiophene (0.15 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (4.0 mL).The reaction mixture was stirred for 16 h at 60 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the productas a colorless oil (97 mg, 72%; r.r. = >98:2).Fe Catalysis: Compound 7f was synthesized according to the GP fromurethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2mmol, 1.2 equiv), 2-methylthiophene (0.29 mL, 3.0 mmol, 3.0 equiv)and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). Thereaction mixture was stirred for 48 h at 40 °C. Purification by chro-matography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as ayellow oil (211 mg, 78%; r.r. = 93:7); Rf = 0.56 cyclohexane/EtOAc =7:3).IR (ATR): 3326 (w), 2985 (w), 2933 (w), 1710 (s), 1506 (s), 1370 (m),1317 (m), 1200 (s), 1094 (w), 1053 (s), 862 (w), 798 (m), 778 cm–1
(m).1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 6.87–6.77 (m, 1H), 6.62–6.51 (m, 1 H), 5.66–5.41 (m, 2 H), 4.31–4.09 (m, 4 H), 2.44 (s,3 H), 1.29–1.19 (m, 6 H).13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 170.3, 155.7,140.6, 136.6, 126.1, 125.2, 62.2, 61.5, 53.8, 15.4, 14.6, 14.2.MS (ESI): m/z [M + Na]+ calcd for C12H17NO4SNa: 294.1; found: 294.4.HRMS (MALDI): m/z [M + K]+ calcd for C12H17NO4SK: 310.0510; found:310.0511.
Ethyl 2-Benzamido-2-(benzofuran-2-yl)acetate (7g)Fe Catalysis: Compound 7g was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), benzofuran (0.33 mL, 3.0 mmol, 3.0 equiv), andFe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-
tion mixture was stirred for 24 h at 60 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 9:1) yielded the product as a yellow solid(166 mg, 51%, r.r. = >98:2).Mp 79.4 °C; Rf = 0.59 (cyclohexane/EtOAc = 7:3).IR (ATR): 3299 (w), 3057 (w), 2991 (w), 1751 (s), 1639 (s), 1602 (w),1579. (w), 1526 (s), 1488 (m), 1454 (m), 1369 (w), 1336 (m), 1241(m), 1206 (s), 1156 (s), 1094 (m), 1016 (m), 961 (m), 820 (m), 749 (s),716 (s), 689 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.89–7.82 (m, 2 H), 7.60–7.42 (m, 5 H),7.35–7.19 (m, 3 H), 6.85 (s, 1 H), 6.09 (d, J = 7.7 Hz, 1 H), 4.37–4.21 (m,2 H), 1.28 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 168.7, 166.8, 155.1, 151.5, 133.6,132.2, 128.8, 128.1, 127.4, 124.9, 123.3, 121.5, 111.5, 106.1, 62.8, 51.3,14.2.MS (ESI): m/z [M + Na]+ calcd for C19H17NO4Na: 346.1; found: 346.2.HRMS (MALDI): m/z [M + H]+ calcd for C19H18NO4: 324.1230; found:324.1229.
Ethyl 2-(Benzofuran-2-yl)-2-[(ethoxycarbonyl)amino]acetate (7h)Bi Catalysis: Compound 7h was synthesized according to the GP fromurethane (46 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg,0.6 mmol, 1.2 equiv), benzofuran (0.16 mL, 1.5 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (4.0 mL). The reactionmixture was stirred for 16 h at 60 °C. Purification by chromatography(cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yellow solid(128 mg, 88%; r.r. = >98:2).Fe Catalysis: Compound 7h was synthesized according to the GP fromurethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), benzofuran (0.32 mL, 3.0 mmol, 3.0 equiv), andFe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 24 h at 60 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yel-low solid (219 mg, 75%; r.r. = 80:20). Further purification of the majorregioisomer could be achieved by precipitation from hexane/CH2Cl2(91:9 mixture of regioisomers, as judged by 1H NMR analysis). Analyt-ical data were obtained for this purified mixture.Mp 60.3 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).IR (ATR): 3263 (w), 2983 (w), 1742 (m), 1688 (s), 1605 (w), 1533 (m),1453 (m), 1369 (m), 1319 (s), 1245 (s), 1200 (s), 1093 (m), 1049 (s),953 (m), 937 (m), 753 cm–1 (s).1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.57–7.52 (m, 1H), 7.49–7.42 (m, 1 H), 7.32–7.19 (m, 2 H), 6.76 (s, 1 H), 5.85–5.72 (m,1 H), 5.71–5.58 (m, 1 H), 4.32–4.10 (m, 4 H), 1.29–1.22 (m, 6 H).13C NMR (75 MHz, CDCl3): δ = 168.7, 155.8, 155.0, 151.8, 128.0, 124.9,123.2, 121.4, 111.5, 105.5, 62.6, 61.7, 52.6, 14.6, 14.2 (peaks not as-signed to regioisomers).MS (ESI): m/z [M + Na]+ calcd for C15H17NO5Na: 314.1; found: 314.2.HMRS (MALDI): m/z [M + H]+ calcd for C15H18NO5: 292.1180; found:292.1177.
Ethyl 2-(Benzamido)-2-(1-tosyl-1H-pyrrol-2-yl)acetate (7i)Fe Catalysis: Compound 7i was synthesized according to the GP frombenzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL,1.2 mmol, 1.2 equiv), N-tosylpyrrole (664 mg, 3.0 mmol, 3.0 equiv),and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The re-action mixture was stirred for 24 h at 60 °C. Purification by chroma-tography (cyclohexane/EtOAc = 9:1) yielded the product as a yellowoil (265 mg, 62%; r.r. = >98:2); Rf = 0.57 (cyclohexane/EtOAc = 7:3).
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IR (ATR): 3365 (w), 1725 (m), 1662 (m), 1599 (w), 1505 (w), 1482 (m),1404 (w), 1363 (m), 1345 (m), 1281 (w), 1246 (w), 1211 (m), 1188(m), 1172 (s), 1155 (s), 1123 (m), 1091 (m), 1056 (m), 1017 (m), 864(w), 808 (m), 750 (s), 716 (m), 702 (m), 673 (s), 627 (m), 584 (s), 562(s), 542 (s), 511 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.68–7.58 (m, 4 H), 7.53–7.36 (m, 3 H),7.33–7.28 (m, 1 H), 7.18–7.11 (m, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.48–6.41 (m, 1 H), 6.31–6.22 (m, 2 H), 4.23–4.06 (m, 2 H), 2.26 (s, 3 H),1.19 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 169.6, 166.5, 145.2, 136.4, 133.5,131.9, 130.1, 129.7, 128.6, 127.3, 126.8, 124.6, 116.9, 112.1, 62.3, 50.1,21.6, 14.1.MS (ESI): m/z [M + Na]+ calcd for C22H22N2O5SNa: 449.1; found: 449.1.HRMS (MALDI): m/z [M + Na]+ calcd for C22H22N2O5SNa: 449.1142;found: 449.1146.
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(1-tosyl-1H-pyrrol-2-yl)ace-tate (7j)Bi Catalysis: Compound 7j was synthesized according to the GP fromurethane (46 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6mmol, 1.2 equiv), N-tosylpyrrole (332 mg, 1.5 mmol, 3.0 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (2.0 mL). The reactionmixture was stirred for 16 h at 60 °C. Purification by chromatography(cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a yellow solid(123 mg, 62%; r.r. = >98:2).Fe CatalysisCompound 7j was synthesized according to the GP from urethane(89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2 mmol,1.2 equiv), N-tosylpyrrole (664 mg, 3.0 mmol, 3.0 equiv), andFe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 24 h at 40 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 9:1 → 4:1) yielded the product as a yel-low solid (302 mg, 75%; r.r. = >98:2).Mp 138.9 °C; Rf = 0.63 (cyclohexane/EtOAc = 7:3).IR (ATR): 3367 (w), 3161 (w), 2985 (w), 1722 (m), 1709 (s), 1596 (w),1515 (m), 1469 (m), 1407 (w), 1364 (m), 1329 (m), 1213 (m), 1176(s), 1154 (s), 1124 (m), 1090 (m), 1048 (s), 899 (m), 813 (m), 739 (m),702 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 2 H), 7.31–7.21 (m, 3H), 6.30 (s, 1 H), 6.25–6.22 (m, 1 H), 5.84 (d, J = 8.1 Hz, 1 H), 5.43 (d, J =6.5 Hz, 1 H), 4.22–4.03 (m, 4 H), 2.40 (s, 3 H), 1.20 (m, 6 H).13C NMR (101 MHz, CDCl3): δ = 169.9, 155.7, 145.2, 136.3, 130.0,129.9, 127.1, 124.3, 116.1, 111.9, 62.1, 61.4, 51.3, 21.7, 14.7, 14.1.MS (ESI): m/z [M + Na]+ calcd for C18H22N2O6SNa: 417.1; found: 417.2.HRMS (MALDI): m/z [M + Na]+ calcd for C18H22N2O6SNa: 417.1096;found: 417.1099.
Ethyl 2-Benzamido-2-(1-tosyl-1H-indol-3-yl)acetate (7k)Fe Catalysis: Compound 7k was synthesized according to the GP frombenzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate (0.12 mL,0.6 mmol, 1.2 equiv), N-tosylindole (407 mg, 1.5 mmol, 3.0 equiv),and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The re-action mixture was stirred for 24 h at 60 °C. Purification by chroma-tography (n-hexane/EtOAc = 9:1 → 4.1 → 7:3) yielded the product as awhite low-melting foam (177 mg, 74%; r.r. = 82:18).Rf = 0.40 (n-hexane/EtOAc = 7:3).
IR (ATR): 1739 (w), 1644 (w), 1520 (w), 1486 (w), 1447 (w), 1367 (m),1171 (s), 1120 (m), 1089 (m), 1019 (m), 979 (m), 812 (w), 746 (m),703 (s), 666 (s), 570 (s), 536 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 8.00–6.90 (m, 15 H), 6.05 (d, J = 7.4 Hz,1 H), 4.40–4.12 (m, 2 H), 2.33 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.6, 166.9, 145.4, 135.3, 135.1,133.6, 132.1, 130.1, 129.9, 128.8, 127.3, 127.1, 125.4, 125.1, 123.8,120.2, 118.0, 113.9, 62.4, 49.6, 21.7, 14.2.MS (ESI): m/z [M + Na]+ calcd for C26H24N2O5SNa: 499.1; found: 499.1.HRMS (MALDI): m/z [M + Na]+ calcd for C26H24N2O5SNa: 499.1298;found: 499.1291.
Ethyl 2-[(Ethoxycarbonyl)amino]-2-(1-tosyl-1H-indol-3-yl)ace-tate (7l)Bi Catalysis: Compound 7l was synthesized according to the GP fromurethane (46 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (61 mg, 0.6mmol, 1.2 equiv), N-tosylindole (203 mg, 0.75 mmol, 1.5 equiv), andBi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in DCE (4.0 mL). The reactionmixture was stirred for 16 h at 60 °C. Purification by chromatography(cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a colorless oil(171 mg, 78%; r.r. = >98:2).Fe Catalysis: Compound 7l was synthesized according to the GP fromurethane (89 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (0.24 mL, 1.2mmol, 1.2 equiv), N-tosylindole (814 mg, 3.0 mmol, 3.0 equiv), andFe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2 (4.0 mL). The reac-tion mixture was stirred for 24 h at 60 °C. Purification by chromatog-raphy (cyclohexane/EtOAc = 9:1 → 4.1) yielded the product as a color-less oil (369 mg, 83%; r.r. = >98:2). Compound 7l is very sensitive, es-pecially towards light or acid and decomposes rapidly. Partialdecomposition (<5%) is observed upon silica gel chromatography. An-alytically pure 7l could be obtained by preparative HPLC (column:Machery Nagel Nuc 50-100/250 × 20 mm, hexane/EtOAc/CH2Cl2 =10:1.5:2, flow rate 8 mL/min) and has to be stored under argon, pro-tected from light at or below –20 °C.Rf = 0.59 (cyclohexane/EtOAc = 7:3).IR (ATR): 3383 (w), 2981 (w), 1714 (m), 1596 (w), 1514 (w), 1446 (m),1368 (m), 1301 (m), 1218 (m), 1171 (s), 1200 (m), 1093 (m), 1050(m), 1019 (m), 976 (m), 856 (w), 812 (m), 745 (s), 704 (m), 663 cm–1
(s).1H NMR (500 MHz, CDCl3): δ = 7.95 (d, J = 8.3 Hz, 1 H), 7.75 (d, J = 8.4Hz, 2 H), 7.64 (d, J = 7.9 Hz, 1 H), 7.58 (s, 1 H), 7.27 (t, J = 32.8 Hz, 4 H),5.68–5.42 (m, 2 H), 4.27–4.08 (m, 4 H), 2.34 (s, 3 H), 1.27–1.16 (m, 6H).13C NMR (126 MHz, CDCl3): δ = 170.5, 155.8, 145.3, 135.3, 135.1,130.1, 128.6, 127.0, 125.3, 124.8, 123.6, 120.2, 118.2, 113.8, 62.2, 61.5,50.8, 21.7, 14.6, 14.1.MS (ESI): m/z [M + Na]+ calcd for C22H24N2O6SNa: 467.1; found: 467.2.HRMS (MALDI): m/z [M + Na]+ calcd for C22H24N2O6SNa: 467.1247;found: 467.1239.
Isopropyl 2-Benzamido-2-mesitylacetate (11a)Bi Catalysis: Compound 11a was synthesized according to the GPfrom benzamide (66 mg, 0.55 mmol, 1.0 equiv), isopropyl 2-oxoace-tate (75 mg 0.65 mmol, 1.18 equiv), mesitylene (0.21 mL, 3.0 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded the prod-uct as colorless solid (94 mg, 50%).
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Fe Catalysis: Compound 11a was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), isopropyl 2-oxoace-tate (174 mg, 1.5 mmol, 1.5 equiv), mesitylene (0.42 mL, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (18 mg, 0.050 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 60 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1 → 1:1) yielded theproduct as a colorless solid (281 mg, 83%).Mp 101.2 °C; Rf = 0.56 (cyclohexane/EtOAc = 7:3).IR (ATR): 3317 (m), 2975 (w), 2932 (w), 1747 (s), 1633 (s), 1579 (w),1530 (s), 1490 (m), 1462 (m), 1360 (m), 1212 (s), 1154 (m), 1108 (s),1089 (s), 973 (w), 852 (m), 828 (w), 787 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2 H), 7.53–7.39 (m, 3 H),7.18 (d, J = 6.2 Hz, 1 H), 6.83 (s, 2 H), 6.15 (d, J = 6.6 Hz, 1 H), 5.08(hept, J = 6.3 Hz, 1 H), 2.47 (s, 6 H), 2.25 (s, 3 H), 1.25 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.2 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.4, 166.6, 137.6, 137.0, 134.2,131.8, 131.1, 130.1, 128.7, 127.2, 69.9, 53.0, 21.8, 21.6, 21.0, 20.5.MS (ESI): m/z [M + Na]+ calcd for C21H25NO3Na: 362.2; found: 362.3.HRMS (MALDI): m/z [M + H]+ calcd for C21H26NO3: 340.1907; found:340.1905.
2-Benzamido-2-mesitylacetic Acid (11b)Fe Catalysis: Compound 11b was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (50%w/w in H2O, 0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,1.5 mmol, 3.0 equiv), and FeCl3·6H2O (7 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (CH2Cl2/MeOH = 20:1 → 9:1) yieldedthe product as a low-melting solid (120 mg, 81%).Bi Catalysis: Compound 11b was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), glyoxylic acid (50%w/w in H2O, 0.13 mL, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL,3.0 mmol, 3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) inMeNO2 (4.0 mL). The reaction mixture was stirred for 21 h at 80 °C.After cooling to r.t., aq 1 M NaOH (15 mL) was added to the reactionmixture. The aqueous phase was washed with EtOAc (2 × 10 mL),acidified with aq 2 N HCl to pH 4, and extracted with EtOAc (3 ×10 mL). The combined organic layers were dried (anhyd MgSO4), fil-tered, and evaporated to dryness. Purification by chromatography(CH2Cl2/MeOH = 20:1 → 9:1) yielded the product as a low-melting sol-id (211 mg, 71%).Mp <30 °C; Rf = 0.41 (CH2Cl2/MeOH = 9:1).IR (ATR): 3412 (w), 2920 (w), 2520 (w), 1732 (m), 1612 (s), 1575 (m),1514 (s), 1485 (s), 1344 (w), 1308 (w), 1240 (m), 1193 (m), 1085 (w),976 (w), 851 (m), 746 (m), 713 cm–1 (s).1H NMR (300 MHz, DMSO-d6): δ = 8.50 (d, J = 6.7 Hz, 1 H), 7.88 (d, J =7.0 Hz, 2 H), 7.56–7.42 (m, 3 H), 6.85 (s, 2 H), 5.94 (d, J = 6.7 Hz, 1 H),2.35 (s, 6 H), 2.21 (s, 3 H).13C NMR (75 MHz, DMSO-d6): δ = 172.5, 166.4, 137.2, 136.5, 133.8,131.4, 131.4, 129.3, 128.2, 127.7, 52.2, 20.4, 20.1.MS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.1; found: 298.5.HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found:298.1440.
2-[(Ethoxycarbonyl)amino]-2-mesitylacetic Acid (11c)Bi Catalysis: Compound 11c was synthesized according to the GPfrom urethane (45 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL,0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), and
Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 24 h at 80 °C. Purification by chromatography(CH2Cl2/MeOH = 50:1 → 20:1) yielded the product as a colorless solid(66 mg, 50%).Fe Catalysis: Compound 11c was synthesized according to the GPfrom urethane (45 mg, 0.5 mmol, 1.0 equiv), glyoxylic acid (0.07 mL,0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol, 3.0 equiv), andFeCl3·6H2O (7 mg, 0.025 mmol, 5 mol%) in MeNO2 (2.0 mL). The reac-tion mixture was stirred for 24 h at 80 °C. Purification by chromatog-raphy (CH2Cl2/MeOH = 50:1 → 20:1) yielded the product as a colorlesssolid (122 mg, 92%).Mp 144.5 °C; Rf = 0.23 (CH2Cl2/MeOH = 9:1).IR (ATR): 3267 (w), 3027 (w), 2918 (w), 2530 (w), 1725 (s), 1655 (m),1613 (m), 1513 (w), 1426 (w), 1336 (m), 1226 (w), 1196 (m), 1067(m), 925 (m), 851 cm–1 (m).1H NMR (400 MHz, DMSO): δ = 12.78 (s, 1 H), 7.42 (d, J = 7.2 Hz, 1 H),6.81 (s, 2 H), 5.52 (d, J = 7.7 Hz, 1 H), 4.09–3.94 (m, 2 H), 2.26 (s, 6 H),2.19 (s, 3 H), 1.16 (t, J = 7.0 Hz, 3 H).13C NMR (101 MHz, DMSO): δ = 172.8, 156.1, 136.7, 136.4, 132.0,129.2, 60.0, 52.9, 20.4, 19.9, 14.6.MS (ESI): m/z [M]+ calcd for C14H19NO4: 265.1; found: 264.2.HRMS (MALDI): m/z [M + Na]+ calcd for C14H19NO4Na: 288.1206;found: 288.1208.
2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-mesitylacetic Acid (11d)Bi Catalysis: Compound 11d was synthesized according to the GPfrom 9H-fluoren-9-yl carbamate (113 mg, 0.5 mmol, 1.0 equiv), gly-oxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in Me-NO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Puri-fication by chromatography (cyclohexane/EtOAc =7:3 → 1:1) yieldedthe product as a colorless oil (94 mg, 45%).Fe Catalysis: Compound 11d was synthesized according to the GPfrom 9H-fluoren-9-yl carbamate (113 mg, 0.5 mmol, 1.0 equiv), gly-oxylic acid (0.07 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,1.5 mmol, 3.0 equiv), and FeCl3·6H2O (9 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc =7:3 → 1:1)yielded the product as a colorless oil (177 mg, 85%); Rf = 0.35 (EtOAc).IR (ATR): 3347 (w), 2953 (w), 1717 (s), 1598 (w), 1512 (m), 1443 (m),1323 (m), 1194 (s), 1052 (s), 853 (m), 747 (s), 616 cm–1 (m).1H NMR (500 MHz, DMSO-d6): δ = 12.84 (s, 1 H), 7.90–7.86 (m, 2 H),7.86–7.81 (m, 1 H), 7.81–7.70 (m, 2 H), 7.44–7.38 (m, 2 H), 7.35–7.26(m, 2 H), 6.83 (s, 2 H), 5.52 (d, J = 7.6 Hz, 1 H), 4.32–4.16 (m, 3 H), 2.28(s, 6 H), 2.20 (s, 3 H).13C NMR (126 MHz, DMSO-d6): δ = 172.8, 156.1, 144.0, 143.7, 140.7,136.9, 136.5), 131.9, 129.3, 127.7, 127.1, 127.0, 125.5, 120.1, 65.9,53.1, 46.7, 20.4, 20.0.MS (ESI): m/z [M + H]+ calcd for C26H26NO4: 416.2; found: 416.4.HRMS (MALDI): m/z [M + Na]+ calcd for C26H25NO4Na: 438.1676;found: 438.1674.
Ethyl 2-Benzamido-2-(2-methoxy-5-pivalamidophenyl)acetate (12a)Fe Catalysis: Compound 12a was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), N-(4-methoxyphenyl)pivalamide
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(311 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol,5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 hat 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 →4:1 → 7:3 → 1:1) yielded the product as a colorless solid (184 mg,89%; r.r.= >98:2).Bi Catalysis: Compound 12a was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), N-(4-methoxyphenyl)pivalamide(311 mg, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.025 mmol,5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 hat 80 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1 →4:1 → 7:3 → 1:1) yielded the product as a colorless solid (128 mg,62%; r.r. = >98:2).Mp 90.2 °C; Rf = 0.20 (cyclohexane/EtOAc = 7:3).IR (ATR): 3302 (w), 2948 (w), 1743 (m), 1638 (s), 1603 (w), 1526 (s),1414 (w), 1369 (w), 1328 (m), 1216 (s), 1149 (m), 1096 (m), 1029(m), 932 (w), 859 (w), 806 (w), 725 (m), 693 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.84–7.76 (m, 3 H), 7.52–7.39 (m, 3 H),7.34–7.30 (m, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 5.84 (d, J = 8.0 Hz, 1 H),4.25–4.16 (m, 2 H), 3.83 (s, 3 H), 1.30 (s, 9 H), 1.20 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 176.7, 171.9, 166.7, 153.8, 134.2,131.8, 131.5, 128.7, 127.3, 126.1, 123.2, 122.2, 111.7, 61.9, 56.0, 53.9,39.6, 27.8, 14.3.MS (ESI): m/z [M + H]+ calcd for C23H29N2O5: 413.2; found: 413.9.HRMS (MALDI): m/z [M + H]+ calcd for C23H29N2O5: 413.2071; found:413.2071.
Ethyl 2-Benzamido-2-(4-methoxy-3-pivalamidophenyl)acetate (12b)Fe Catalysis: Compound 12b was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), N-(2-methoxyphenyl)pivalamide(311 mg, 1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mol,5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 hat 100 °C. Purification by chromatography (cyclohexane/EtOAc = 9:1→ 4:1 → 7:3 → 1:1) yielded the product as a colorless solid (164 mg,80%, obtained as a 1.6:1 mixture of regioisomers). Further purifica-tion of the major regioisomer could be achieved by precipitation fromhexane/CH2Cl2 (92:8 mixture of regioisomers, as judged by 1H NMRanalysis). Analytical data were obtained for this purified mixture.Mp 127.6 °C; Rf = 0.34 (cyclohexane/EtOAc = 7:3).IR (ATR): 3443 (w), 3283 (w), 2959 (w), 2361 (w), 1743 (m), 1668 (m),1632 (m), 1600 (w), 1579 (w), 1525 (s), 1484 (s), 1430 (m), 1394 (w),1339 (m), 1267 (m), 1198 (m), 1153 (m), 1122 (m) 1093 (w), 1027cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 2.2 Hz, 1 H), 8.10 (s, 1 H),7.85–7.79 (m, 2 H), 7.52–7.39 (m, 3 H), 7.19–7.11 (m, 2 H), 6.86 (d, J =8.4 Hz, 1 H), 5.68 (d, J = 7.0 Hz, 1 H), 4.33–4.12 (m, 2 H), 3.89 (s, 3 H),1.31 (s, 9 H), 1.24 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 176.6, 171.1, 166.7, 148.1, 134.0,131.8, 129.7, 128.7, 128.5, 127.4, 123.10, 118.2, 110.1, 62.1, 56.9, 56.1,40.2, 27.8, 14.2.MS (ESI): m/z [M + Na]+ calcd for C23H28N2O5Na: 435.2; found: 435.3.HRMS (MALDI): m/z [M + H]+ calcd for C23H29N2O5: 413.2071; found:413.2072.
Ethyl 2-Benzamido-2-(4-methyl-3-pivalamidophenyl)acetate (12c)Bi Catalysis: Compound 12c was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), 2-methylpivalanilide (287 mg,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (16 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.Purification by chromatography (n-hexane/EtOAc = 4:1) yielded theproduct as a yellow solid (89 mg, 45%; r.r. = >98:2).Fe Catalysis: Compound 12c was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), 2-methylpivalanilide (287 mg,1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 100 °C.Purification by chromatography (n-hexane/EtOAc = 4:1) yielded theproduct as a yellow solid (152 mg, 77%; r.r. = 91:9).Mp 123–125 °C; Rf = 0.5 (n-hexane/EtOAc = 1:1).IR (ATR): 2959 (w), 2923 (m), 2853 (w), 1744 (s), 1661 (s), 1643 (s),1615 (w), 1602 (w), 1580 (w), 1519 (s), 1489 (s), 1446 (m), 1417 (w),1399 (w), 1367 (m), 1340 (s), 1299 (s), 1265 (s), 1218 (m), 1194 (s),1170 (s), 1092 (m), 1023 (m), 947 (w), 923 (w), 880 (w), 800 (w), 777(m), 749 (w), 714 (s), 691 (s), 620 (s), 608 (s), 584 (s), 540 cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 9.0 Hz, 1 H), 7.82–7.79 (m, 2H), 7.51–7.41 (m, 3 H), 7.28 (s, 2 H), 7.23 (br s, 1 H), 7.12 (br d, J = 6.8Hz, 1 H), 5.68 (d, J = 6.9 Hz, 1 H), 4.30–4.13 (m, 2 H), 2.26 (s, 3 H), 1.33(s, 9 H), 1.24 (t, J = 5.8 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 176.6, 171.2, 166.6, 136.3, 133.9, 133.1,132.0, 129.7, 129.14, 128.7, 127.3, 125.8, 123.2, 62.2, 56.6, 40.0, 27.8,17.8, 14.2.MS (ESI): m/z [M + Na]+ calcd for C23H28N2O4Na: 420.0; found: 420.0.HRMS (MALDI): m/z [M + K]+ calcd for C23H28N2O4K: 435.1681; found:435.1674.
Ethyl 2-Benzamido-2-(2,5-dimethoxyphenyl)acetate (12d)Fe Catalysis: Compound 12d was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), 1,4-dimethoxybenzene (207 mg,1.5 mmol, 3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (cyclohexane/EtOAc = 4:1) yieldedthe product as a colorless solid (128 mg, 74%).Mp 75.4 °C; Rf = 0.33 (cyclohexane/EtOAc = 7:3).IR (ATR): 3299 (w), 2954 (w), 2835 (w), 1727 (m), 1636 (m), 1581 (w),1503 (s), 1458 (m), 1327 (m), 1207 (s), 1153 (s), 1045 (s), 1022 (s),925 (m), 822 (m), 755 (m), 715 (m), 635 cm–1 (m).1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2 H), 7.51–7.46 (m, 1 H),7.42 (t, J = 7.4 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 1 H), 7.01 (s, 1 H), 6.84 (d, J =1.3 Hz, 2 H), 5.90 (d, J = 8.3 Hz, 1 H), 4.26–4.16 (m, 2 H), 3.82 (s, 3 H),3.78 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.1, 166.7, 153.9, 151.4, 134.3,131.7, 128.7, 127.3, 126.7, 116.7, 114.5, 112.4, 61.8, 56.3, 55.9, 54.1,14.3.MS (ESI): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1; found: 366.2.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO5: 344.1493; found:344.1491.Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.20,H, 6.11; N, 3.80.
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Ethyl 2-Benzamido-2-(3,4-dimethoxyphenyl)acetate (12e)Fe Catalysis: Compound 12e was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(0.24 mL, 1.2 mmol, 1.2 equiv), veratrole (0.38 mL, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a colorless oil (216 mg, 63%; r.r. = >98:2).Rf = 0.32 (cyclohexane/EtOAc = 7:3).IR (ATR): 3338 (w), 2980 (w), 1732 (s), 1634 (s), 1595 (w), 1578 (w),1520 (s), 1488 (m), 1467 (m), 1356 (m), 1332 (m), 1255 (s), 1238 (m),1203 (m), 1183 (m), 1165 (m), 1139 (s), 1097 (m), 1017 (s), 923 (w),878 (w), 851 (m), 799 (m), 752 (m), 714 (s), 691 (m), 633 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.3 Hz, 2 H), 7.51 (t, J = 7.3Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.11 (d, J = 6.7 Hz, 1 H), 7.02–6.94 (m,2 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.69 (d, J = 7.0 Hz, 1 H), 4.33–4.15 (m, 2H), 3.89 (s, 3 H), 3.87 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 171.3, 166.7, 149.4, 149.4, 133.9,132.0, 129.3, 128.8, 127.3, 119.7, 111.5, 110.7, 62.1, 56.7, 56.1, 56.1,14.2.MS (ESI): m/z [M + Na]+ calcd for C19H21NO5Na: 366.1; found: 366.3.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO5: 344.1493; found:344.1490.Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.31;H, 6.18; N, 3.98.
Ethyl 2-(Anthracen-9-yl)-2-benzamidoacetate (12f)Bi Catalysis: Compound 12f was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), anthracene (267 mg, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1) yielded theproduct as a yellow solid (92 mg, 48%; r.r. = >98:2).Fe Catalysis: Compound 12f was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), anthracene (267 mg, 1.5 mmol,3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 20:1 → 9:1 → 4:1)yielded the product as a yellow solid (157 mg, 82%; r.r. = >98:2).Mp 128.6 °C; Rf = 0.59 (cyclohexane/EtOAc = 7:3).IR (ATR): 3355 (w), 3058 (w), 2979 (w), 1721 (s), 1640 (s), 1579 (w),1520 (s), 1488 (m), 1450 (m), 1367 (w), 1314 (s), 1210 (s), 1142 (m),1092 (m), 1044 (m), 901 (m), 845 (m), 727 (s), 713 (s), 690 cm–1 (s).1H NMR (500 MHz, CDCl3): δ = 8.55–8.43 (m, 3 H), 8.06 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2 H), 7.64–7.34 (m, 9 H), 7.31 (d, J = 7.2 Hz, 1 H),4.25–4.09 (m, 2 H), 1.04 (t, J = 7.1 Hz, 3 H).13C NMR (126 MHz, CDCl3): δ = 172.3, 167.3, 133.8, 131.9, 131.8,130.3, 129.8, 129.4, 128.7, 128.1, 127.37, 127.3, 125.3, 123.6, 62.3,51.4, 14.1.MS (ESI): m/z [M + H]+ calcd for C25H22NO3: 384.2; found: 385.0.HRMS (MALDI): m/z [M] calcd for C25H21NO3: 383.1521; found:383.1501.
Ethyl 2-Benzamido-2-(5-bromo-2-hydroxyphenyl)acetate (12g)Bi Catalysis: Compound 12g was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), 4-bromophenol (260 mg, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (3 mg, 0.005 mmol, 1 mol%) in DCE (2.0 mL).The reaction mixture was stirred for 16 h at 80 °C. Purification bychromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded the productas a low-melting solid (123 mg, 65%; r.r. = >98:2).Fe Catalysis: Compound 12g was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(0.24 mL, 1.2 mmol, 1.2 equiv), 4-bromophenol (516 mg, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a low-melting solid (39 mg, 11%; r.r. = >98:2).Rf = 0.46 (cyclohexane/EtOAc = 7:3).IR (ATR): 3368, 3099, 2920, 2852, 1736, 1622, 1576, 1530 (s), 1488(m), 1430 (m), 1363, 1344 (m), 1310 (m), 1278 (s), 1236 (m), 1198(m), 1120 (m), 1090 (s), 1022 (m), 877 (m), 813 (s), 727 (s), 692 cm–1
(m).1H NMR (400 MHz, CDCl3): δ = 9.47 (s, 1 H), 7.86–7.76 (m, 2 H), 7.61(d, J = 6.7 Hz, 1 H), 7.58–7.52 (m, 1 H), 7.49–7.43 (m, 2 H), 7.35–7.31(m, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 5.83 (d, J = 6.9Hz, 1 H), 4.39–4.30 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.6, 168.3, 155.0, 133.3, 132.7,132.0, 129.9, 128.8, 127.3, 126.1, 121.3, 112.6, 62.9, 51.8, 14.0.MS (ESI): m/z [M + Na]+ calcd for C17H16BrNO4Na: 400.0; found: 400.1.HRMS (MALDI): m/z [M + H]+ calcd for C17H17BrNO4: 378.0335; found:378.0335.
Ethyl 2-Benzamido-2-(3,4-dimethylphenyl)acetate (12h)Bi Catalysis: Compound 12h was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(122 mg, 1.2 mmol, 1.2 equiv), o-xylene (0.36 mL, 3.0 mmol,3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-tion by chromatography (n-hexane/EtOAc = 4:1) yielded the productas a colorless solid (278 mg, 89%; r.r. = 89:11). Fe Catalysis: Compound 12h was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), o-xylene (0.18 mL, 1.5 mmol,3.0 equiv), and Fe(ClO4)3 (9 mg, 0.025 mmol, 5 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-uct as a colorless solid (88 mg, 54%; r.r. = 80:20). Further purificationof the major regioisomer could be achieved by precipitation fromhexane/CH2Cl2 (87:13 mixture of regioisomers, as judged by 1H NMRanalysis). Analytical data were obtained for this purified mixture.Mp 70–72 °C; Rf = 0.31 (cyclohexane/EtOAc = 7:3).IR (ATR): 3285 (w), 2981 (w), 1741 (s), 1635 (s), 1602 (w), 1579 (w),1527 (s), 1488 (s), 1446 (w), 1370 (w), 1345 (m), 1302 (m), 1263 (m),1189 (s), 1153 (s), 1093 (m), 1022 (m), 819 (w), 689 cm–1 (s).1H NMR (400 MHz, CDCl3): δ (major regioisomer) = 7.82 (d, J = 7.3 Hz,2 H), 7.54–7.39 (m, 3 H), 7.22–6.95 (m, 4 H), 5.71 (d, J = 7.1 Hz, 1 H),4.34–4.10 (m, 2 H), 2.26 (s, 3 H), 2.25 (s, 3 H), 1.27–1.21 (m, 3 H).13C NMR (101 MHz, CDCl3): δ (major regioisomer) = 171.4, 166.6,137.5, 137.2, 134.3, 134.0, 131.9, 130.3, 128.7, 127.3, 124.8, 124.4,62.1, 56.8, 20.0, 19.6, 14.2.
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MS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.2; found: 312.2.HRMS (MALDI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:312.1595.
Ethyl 2-Benzamido-2-(5-chloro-2-methoxyphenyl)acetate (12i)Bi Catalysis: Compound 12i was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(122 mg, 1.2 mmol, 1.2 equiv), 4-chloroanisole (0.49 mL, 4.0 mmol,4.0 equiv), and Bi(OTf)3 (32 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 16 h at 100 °C. Purifica-tion by chromatography (n-hexane/EtOAc = 4:1) yielded the productas a colorless solid (310 mg, 89%; r.r. = >98:2).Fe Catalysis: Compound 12i was synthesized according to the GPfrom benzamide (121 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(0.24 mL, 1.2 mmol, 1.2 equiv), 4-chloroanisole (0.37 mL, 3.0 mmol,3.0 equiv), and Fe(ClO4)3 (18 mg, 0.05 mmol, 5 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 9:1 → 4:1) yielded theproduct as a colorless solid (116 mg, 34%; r.r. = >98:2).Mp 88.8 °C; Rf = 0.55 (cyclohexane/EtOAc = 7:3).IR (ATR): 3257 (w), 2959 (w), 1737 (s), 1638 (s), 1602 (w), 1579 (w),1523 (m), 1488 (s), 1458 (m), 1365 (w), 1320 (m), 1247 (s), 1190 (s),1130 (m), 1093 (s), 1026 (s), 979 (w), 804 (m), 719 (m), 658 cm–1 (s).1H NMR (400 MHz, CDCl3): δ = 7.79 (dd, J = 5.2, 3.3 Hz, 2 H), 7.53–7.40(m, 4 H), 7.30–7.23 (m, 2 H), 6.83 (d, J = 8.8 Hz, 1 H), 5.88 (d, J = 8.0 Hz,1 H), 4.24–4.17 (m, 2 H), 3.85 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).13C NMR (101 MHz, CDCl3): δ = 170.6, 166.5, 155.7, 134.0, 131.7,130.6, 129.4, 128.6, 127.4, 127.2, 125.9, 112.3, 61.9, 56.0, 53.3, 14.1.MS (ESI): m/z [M + H]+ calcd for C18H19ClNO4: 348.1; found: 348.2.HRMS (MALDI): m/z [M + H]+ calcd for C18H19ClNO4: 348.0997; found:348.0995.
Ethyl 2-Benzamido-2-(p-tolyl)acetate (12j)Bi Catalysis: Compound 12j was synthesized according to the GPfrom benzamide (61 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(61 mg, 0.6 mmol, 1.2 equiv), toluene (0.22 mL, 2.1 mmol, 4.2 equiv),and Bi(OTf)3 (7 mg, 0.005 mmol, 2 mol%) in DCE (2.0 mL). The reac-tion mixture was stirred for 16 h at 100 °C. Purification by chroma-tography (n-hexane/EtOAc = 4:1) yielded the product as a colorlesssolid (74 mg, 50%; r.r. = 75:25).Mp 99–101 °C; Rf = 0.4 (n-hexane/EtOAc 4:1).IR (ATR): 3290 (w), 1743 (s), 1636 (s), 1603 (m), 1581 (m), 1527 (s),1488 (s), 1447 (m), 1372 (m), 1348 (m), 1330 (m), 1300 (w), 1275(w), 1252 (m), 1206 (s), 1178 (s), 1153 (s), 1096 (m), 1075 (w), 1021(s), 928 (w), 815 (m), 803 (w), 791 (w), 759 (m), 723 (s), 711 (s), 691(s), 634 (m), 615 (m), 587 (s), 573 (m), 512 (m), 487 (m), 459 cm–1
(w).1H NMR (300 MHz, CDCl3): δ (major regioisomer) = 7.83–7.80 (m, 2H), 7.54–7.40 (m, 3 H), 7.35–7.32 (m, J = 8.1 Hz, 2 H), 7.24–7.16 (m, J =15.2, 5.8 Hz, 2 H), 7.11 (br d, J = 6.9 Hz, 1 H), 5.73 (d, J = 7.0 Hz, 1 H),4.33–4.11 (m, 2 H), 2.34 (s, 3 H), 1.29–1.19 (m, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.33, 166.61, 138.51, 137.19, 135.48,133.94, 131.93, 131.17, 129.81, 128.73, 128.60, 127.34, 127.28,126.67, 126.45, 62.12, 56.75, 53.71, 21.30, 19.68, 14.18. (peaks are notassigned to regioisomers).MS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.5; found: 298.5.HRMS (MALDI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found:298.1439.
Ethyl 2-Mesityl-2-(2-oxopyrrolidin-1-yl)acetate (14a)Bi Catalysis: Compound 14a was synthesized according to the GPfrom pyrrolidin-2-one (85 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-uct as a colorless solid (182 mg, 63%).Fe Catalysis: Compound 14a was synthesized according to the GPfrom pyrrolidin-2-one (43 mg, 0.5 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and FeCl3·6H2O (3 mg, 0.01 mmol, 2 mol%) in MeNO2(2.0 mL). The reaction mixture was stirred for 24 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-uct as a colorless solid (12 mg, 8%).Mp 141–142 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).IR (ATR): 2988 (w), 2926 (w), 1743 (s), 1681 (s), 1610 (m), 1491 (m),1460 (m), 1245 (m), 1187 (s), 1023 (m), 903 (w), 860 (m), 673 cm–1
(m).1H NMR (300 MHz, CDCl3): δ = 6.87 (s, 2 H), 6.12 (s, 1 H), 4.33–4.11(m, 2 H), 3.66 (m, 1 H),2.93 (m, 1 H), 2.56–2.35 (m, 2 H), 2.26 (d, J = 4.5 Hz, 9 H), 2.10–1.99(m, 1 H), 1.86–1.79 (m,1 H), 1.24 (t, J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 175.3, 171.7, 138.1, 130.1, 128.2, 61.8,54.0, 44.2, 30.8, 21.0, 20.6, 18.3, 14.2.MS (ESI): m/z [M + H]+ calcd for C17H24NO3: 290.2; found: 290.2.Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.47;H, 7.97; N, 4.66.
Ethyl 2-Mesityl-2-(2-oxooxazolidin-3-yl)acetate (14b)Bi Catalysis: Compound 14b was synthesized according to the GPfrom oxazolidin-2-one (87 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(122 mg, 1.2 mmol, 1.2 equiv), mesitylene (0.42 mL, 3.0 mmol,3.0 equiv), and Bi(OTf)3 (13 mg, 0.02 mmol, 2 mol%) in MeNO2(4.0 mL). The reaction mixture was stirred for 16 h at 80 °C. Purifica-tion by chromatography (cyclohexane/EtOAc = 4:1) yielded the prod-uct as a colorless solid (234 mg, 80%).Mp 127–128 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).IR (ATR): 2921 (w), 1732 (s), 1611 (w), 1486 (w), 1447 (m), 1239 (m),1144 (w), 1023 (s), 884 (m), 738 (w), 699 (m), 676 cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 6.89 (s, 2 H), 5.88 (s, 1 H), 4.45–4.14(m, 4 H), 3.93 (m, 1 H), 3.13 (m, 1 H), 2.28 (d, J = 2.7 Hz, 9 H), 1.26 (t,J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.4, 158.4, 138.6, 137.9, 130.3, 127.8,62.5, 62.1, 55.6, 41.9, 21.0, 20.5, 14.3.MS (ESI): m/z [M + H]+ calcd for C16H22NO4: 292.2; found: 292.2.Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 65.82;H, 7.25; N, 4.69.
Ethyl 2-Mesityl-2-(methylsulfonamido)acetate (16a)Bi Catalysis: Compound 16a was synthesized according to the GPfrom methanesulfonamide (49 mg, 0.5 mmol, 1.0 equiv), ethyl glyox-alate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL, 1.5 mmol,3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) in MeNO2 (2.0 mL).
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The reaction mixture was stirred for 20 h at 80 °C. Purification bychromatography (n-hexane/EtOAc = 4:1) yielded the product as a col-orless solid (81 mg, 54%).Mp 126–128 °C; Rf = 0.5 (n-hexane/EtOAc 7:3).IR (ATR): 3298 (w), 2966 (w), 2927 (w), 2111 (w), 1732 (s), 1609 (w),1464 (w), 1413 (m), 1401 (m), 1366 (w), 1327 (s), 1311 (s), 1289 (s),1254 (m), 1219 (s), 1199 (s), 1161 (s), 1145 (s), 1096 (s), 1021 (m),987 (s), 970 (s), 909 (w), 872 (m), 855 (s), 827 (m), 784 (w), 762 (s),721 (w), 636 (w), 602 (m), 555 (m), 528 (s), 513 (s), 475 cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 6.86 (s, 2 H), 5.64 (d, J = 4.0 Hz, 1 H),5.41 (br d, J = 3.5 Hz, 1 H), 4.29–4.13 (m, 2 H), 2.61 (s, 3 H), 2.35 (s, 6H), 2.26 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.21, 138.51, 137.35, 130.28, 129.78,62.68, 55.24, 42.03, 21.04, 20.10, 14.20.MS (ESI): m/z [M + Na] calcd for C14H21NO4SNa: 322.1; found: 322.0.HRMS (MALDI): m/z [M + K]+ calcd for C14H21NO4SK: 338.0823; found:338.0823.
Ethyl 2-Mesityl-2-(4-methylphenylsulfonamido)acetate (16b, R = Me)Bi Catalysis: Compound 16b was synthesized according to the GPfrom 4-methylbenzenesulfonamide (87 mg, 0.5 mmol, 1.0 equiv),ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (n-hexane/EtOAc = 9:1 → 4:1) yieldedthe product as a colorless solid (148 mg, 79%).Mp 138–140 °C; Rf = 0.3 (cyclohexane/EtOAc = 4:1).IR (ATR): 3275 (w), 2923 (w), 1735 (s), 1611 (w), 1597 (w), 1451 (w),1407 (w), 1367 (w), 1330 (m), 1289 (m), 1265 (m), 1228 (m), 1187(w), 1163 (s), 1119 (w), 1095 (w), 1065 (m), 1023 (m), 972 (w), 938(w), 911 (m), 870 (m), 838 (w), 825 (w), 809 (s), 778 (w), 721 (m),705 (w), 670 (m), 586 (s), 552 (s), 530 (m), 486 cm–1 (w).1H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 8.3 Hz, 2 H), 7.07 (d, J = 8.1Hz, 2 H), 6.65 (s, 2 H), 5.69 (d, J = 4.6 Hz, 1 H), 5.51 (d, J = 4.7 Hz, 1 H),4.20–4.03 (m, 2 H), 2.34 (s, 3 H), 2.21 (s, 6 H), 2.21 (s, 3 H), 1.12 (t, J =7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 170.93, 143.13, 137.99, 137.18, 137.13,129.84, 129.46, 129.17, 126.99, 62.55, 55.01, 21.59, 20.92, 20.12,14.10.MS (ESI): m/z [M + Na]+ calcd for C20H25NO4SNa: 398.1; found: 398.1.HRMS (MALDI): m/z [M + K]+ calcd for C20H25NO4SK: 414.1136; found:414.1133.
Ethyl 2-(4-Bromophenylsulfonamido)-2-mesitylacetate (16b, R = Br)Bi Catalysis: Compound 16b (R = Br) was synthesized according tothe GP from 4-bromobenzenesulfonamide (120 mg, 0.5 mmol,1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene(0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol,2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 16 hat 100 °C. Purification by chromatography (n-hexane/EtOAc 4:1 →7:3) yielded the product as a colorless solid (118 mg, 54%).Mp 114–116 °C; Rf = 0.6 (n-hexane/EtOAc = 4:1).
IR (ATR): 3309 (w), 2965 (w), 1732 (s), 1610 (w), 1577 (w), 1473 (w),1449 (w), 1391 (m), 1370 (m), 1323 (s), 1299 (m), 1278 (s), 1247 (m),1223 (m), 1200 (m), 1159 (s), 1147 (s), 1090 (s), 1071 (s), 1033 (m),1012 (m), 975 (w), 925 (m), 852 (m), 818 (s), 764 (w), 740 (s), 724(m), 703 (w), 615 (s), 593 (m), 562 (s), 553 (s), 532 (m), 475 cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 7.37–7.30 (m, 4 H), 6.63 (s, 2 H), 5.84(br d, J = 4.2 Hz, 1 H), 5.57 (d, J = 4.3 Hz, 1 H), 4.23–4.06 (m, 2 H), 2.20(s, 6 H), 2.19 (s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 170.65, 139.23, 138.40, 137.17, 131.58,129.83, 128.78, 128.32, 127.12, 62.68, 55.01, 20.88, 20.01, 14.09.MS (ESI): m/z [M + Na]+ calcd for C19H22BrNO4SNa: 462.0; found:462.0.HRMS (MALDI): m/z [M + K]+ calcd for C19H22BrNO4SK: 478.0085;found: 478.0069.
Ethyl 2-Mesityl-2-(4-methoxyphenylsulfonamido)acetate (16b, R = OMe)Bi Catalysis: Compound 16b (R = OMe) was synthesized according tothe GP from 4-methoxybenzenesulfonamide (196 mg, 0.5 mmol,1.0 equiv), ethyl glyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene(0.21 mL, 1.5 mmol, 3.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol,2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 18 hat 80 °C. Purification by chromatography (n-hexane/EtOAc = 4:1)yielded the product as a colorless solid (126 mg, 64%).Mp 173–175 °C; Rf = 0.5 (n-hexane/EtOAc 4:1).IR (ATR): 3274 (w), 2923 (w), 1738 (m), 1594 (m), 1496 (m), 1437 (w),1412 (m), 1329 (m), 1311 (w), 1288 (w), 1263 (s), 1228 (m), 1183(m), 1157 (m), 1119 (w), 1096 (m), 1063 (m), 1024 (s), 939 (w), 913(m), 870 (m), 828 (s), 801 (m), 779 (m), 722 (m), 674 (s), 628 (w), 585(s), 559 cm–1 (s).1H NMR (300 MHz, CDCl3): δ = 7.50–7.45 (m, 2 H), 6.75–6.70 (m, 2 H),6.66 (s, 2 H), 5.67 (br d, J = 4.5 Hz, 1 H), 5.51 (d, J = 4.6 Hz, 1 H), 4.20–4.04 (m, 2 H), 3.80 (s, 3 H), 2.21 (s, 6 H), 2.19 (s, 3 H), 1.13 (t, J = 7.1 Hz,3 H).13C NMR (75 MHz, CDCl3): δ = 170.95, 162.74, 137.90, 137.17, 131.85,129.87, 129.42, 129.09, 113.71, 62.55, 55.66, 55.00, 20.92, 20.13,14.12.MS (ESI): m/z [M + Na]+ calcd for C20H25NO5SNa: 414.1; found:414.08.HRMS (MALDI): m/z [M + Na]+ calcd for C20H25NO5SNa: 414.1346;found: 414.1338.
Ethyl 2-Mesityl-2-(thiophene-2-sulfonamido)acetate (16c)Bi Catalysis: Compound 16c was synthesized according to the GPfrom 2-thiophenesulfonamide (82 mg, 0.5 mmol, 1.0 equiv), ethylglyoxalate (61 mg, 0.6 mmol, 1.2 equiv), mesitylene (0.21 mL,1.5 mmol, 1.5 equiv) and Bi(OTf)3 (7 mg, 0.01 mmol, 2 mol%) inMeNO2 (2.0 mL). The reaction mixture was stirred for 16 h at 80 °C.Purification by chromatography (n-hexane/EtOAc 9:1 → 4:1) yieldedthe product as a colorless solid (123 mg, 67%).Mp 158–160 °C; Rf = 0.3 (n-hexane/EtOAc = 4:1).IR (ATR): 3314 (w), 3115 (w), 2967 (w), 2083 (w), 1739 (s), 1612 (w),1509 (w), 1480 (w), 1463 (w), 1407 (m), 1367 (w), 1329 (s), 1287 (s),1225 (m), 1197 (m), 1157 (s), 1144 (s), 1091 (s), 1033 (m), 1014 (s),976 (w), 925 (w), 852 (s), 828 (m), 782 (w), 739 (m), 729 (s), 666 (s),641 (w), 608 (s), 589 (s), 570 (s), 546 (s), 528 (s), 468 cm–1 (m).
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1H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 5.0, 1.2 Hz, 1 H), 7.24 (dd,J = 3.8, 1.3 Hz, 1 H), 6.88–6.85 (m, 1 H), 6.72 (s, 2 H), 5.87 (br d, J = 4.9Hz, 1 H), 5.59 (d, J = 5.0 Hz, 1 H), 4.22–4.05 (m, 2 H), 2.26 (s, 6 H), 2.21(s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 170.78, 141.13, 138.13, 137.21, 132.19,131.93, 129.96, 129.35, 127.00, 62.67, 55.28, 20.96, 20.16, 14.11.MS (ESI): m/z [M + H]+ calcd for C17H22NO4S2: 368.1; found: 368.5.HRMS (MALDI): m/z [M + K]+ calcd for C17H21NO4S2K: 406.0544;found: 406.0543.
Ethyl 3,5,10,10a-Tetrahydro-3-oxo-1H-oxazolo[3,4-b]isoquinoline-5-carboxylate (21)Bi Catalysis: Compound 21 was synthesized according to the GP from(R)-4-benzyloxazolidin-2-one (59 mg, 0.3 mmol, 1.0 equiv), ethyl gly-oxalate (61 mg, 0.6 mmol, 2.0 equiv), and Bi(OTf)3 (7 mg, 0.01 mmol,2 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 hat 80 °C. Purification by chromatography (cyclohexane/EtOAc = 4:1)yielded the product as a colorless solid (72 mg, 84%).Mp 58–59 °C; Rf = 0.2 (cyclohexane/EtOAc = 7:3).IR (ATR): 2980 (w), 2936 (w), 2084 (w), 1760 (s), 1726 (s), 1477 (m),1454 (m), 1408 (m), 1393 (m), 1365 (m), 1340 (m), 1322 (m), 1272(s), 1237 (s), 1227 (s), 1205 (s), 1186 (s), 1167 (m), 1115 (m), 1099(m), 1063 (s), 1017 (s), 983 (m), 938 (m), 917 (w), 892 (m), 876 (m),824 (m), 810 (m), 759 (s), 745 (m), 715 (w), 697 (m), 671 (m), 620(w), 585 (w), 534 (m), 509 (w), 495 cm–1 (m).1H NMR (300 MHz, CDCl3): δ = 7.61–7.56 (m, 1 H), 7.28–7.25 (m, 3 H),7.18–7.15 (m, 1 H), 5.46 (s, 1 H), 4.72–4.67 (m, 1 H), 4.52–4.45 (m, 1H), 4.27–4.12 (m, 3 H), 3.06–2.99 (m, 1 H), 2.93–2.84 (m, 1 H), 1.31 (t,J = 7.1 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 170.09, 157.14, 132.04, 129.88, 128.95,128.31, 127.65, 127.31, 69.38, 62.16, 55.07, 49.62, 33.78, 14.25.The structure was assigned by COSY.MS (ESI): m/z [M + H]+ calcd for C14H16NO4: 262.1; found: 262.2.Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 63.95;H, 5.82; N, 5.20.
Ethyl 2-(3-Methyl-(1,3-dioxoisoindolin-2-yl)butanamido)-2-mesi-tylacetate (23, PG = Phth)Bi Catalysis: Compound 23 (PG = Phth) was synthesized according tothe GP from 3-methyl-2(1,3-dioxoisoindolin-2-yl)butanamide(246 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate (122 mg, 1.2 mmol,1.2 equiv), mesitylene (0.41 mL, 3.0 mmol, 3.0 equiv), and Bi(OTf)3(13 mg, 0.02 mmol, 2 mol%) in MeNO2 (4.0 mL). The reaction mixturewas stirred for 24 h at 80 °C. Purification by chromatography (n-hex-ane/EtOAc = 4:1) yielded the product as a colorless solid (393 mg,87%; r.r. = 67:33). IR (ATR): 3348 (w), 2966 (w), 2873 (w), 2050 (w), 1979 (w), 1776 (w),1765 (w), 1730 (m), 1705 (s), 1676 (s), 1608 (w), 1525 (s), 1466 (m),1383 (s), 1360 (m), 1331 (m), 1279 (m), 1240 (s), 1153 (m), 1099 (m),1063 (s), 1026 (s), 982 (w), 947 (w), 908 (w), 885 (m), 868 (w), 854(m), 827 (w), 806 (w), 766 (w), 725 (s), 708 (m), 688 (w), 613 (s), 604cm–1 (s).
Diastereomer aMp 63–65 °C; Rf = 0.2 (n-hexane/EtOAc = 4:1).
1H NMR (300 MHz, CDCl3): δ = 8.10 (br d, J = 7.2 Hz, 1 H), 7.90–7.88(m, 2 H), 7.77–7.74 (m, 2 H), 6.83 (s, 2 H), 5.99 (d, J = 7.3 Hz, 1 H), 4.44(d, J = 11.5 Hz, 1 H), 4.20–4.03 (m, 2 H), 2.86–2.74 (m, 1 H), 2.39 (s, 6H), 2.25 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.83(d, J = 6.6 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.38, 168.61, 168.33, 137.69, 137.05,134.54, 131.57, 130.90, 130.01, 123.88, 63.58, 61.85, 52.40, 27.89,21.01, 20.29, 19.62, 14.11.
Diastereomer bMp 136–138 °C; Rf = 0.3 (n-hexane/EtOAc = 4:1).1H NMR (300 MHz, CDCl3): δ = 7.95 (br d, J = 7.4 Hz, 1 H), 7.85–7.82(m, 2 H), 7.74–7.71 (m, 2 H), 6.79 (s, 2 H), 6.04 (d, J = 7.5 Hz, 1 H), 4.45(d, J = 11.3 Hz, 1 H), 4.24–4.09 (m, 2 H), 3.03–2.90 (m, 1 H), 2.36 (s, 6H), 2.21 (s, 3 H), 1.20–1.14 (m, 6 H), 0.86 (d, J = 6.6 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 171.43, 168.54, 168.50, 137.72, 137.08,134.52, 131.51, 130.82, 129.99, 123.84, 63.29, 61.88, 52.10, 27.96,20.97, 20.28, 19.91, 19.72, 14.18.MS (ESI): m/z [M + H]+ calcd for C26H31N2O5: 451.2; found: 451.4.HRMS (MALDI): m/z [M + H]+ calcd for C26H31N2O5: 451.2228; found:451.2224.
Ethyl 2-Benzamido-2-hydroxyacetate (24a)Fe Catalysis: Compound 24a was synthesized according to the GPfrom benzamide (61 mg, 1.0 mmol, 1.0 equiv), ethyl glyoxalate(0.12 mL, 1.2 mmol, 1.2 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol,5 mol%) in MeNO2 (2.0 mL). The reaction mixture was stirred for 24 hat r.t. Purification by chromatography (n-hexane/EtOAc = 4:1) yieldedthe product as a colorless solid (96 mg, 99%).Mp 54.8 °C; Rf = 0.30 (n-hexane/EtOAc = 7:3).1H NMR (400 MHz, CDCl3): δ = 7.84–7.79 (m, 2 H), 7.51 (d, J = 51.2 Hz,3 H), 7.36 (d, J = 5.8 Hz, 1 H), 5.78 (dd, J = 6.9, 6.0 Hz, 1 H), 4.35 (q, J =7.1 Hz, 2 H), 4.15 (d, J = 5.8 Hz, 1 H), 1.36 (t, J = 7.1 Hz, 3 H).Analytical and spectral data are consistent with those reported in theliterature.36
Ethyl 2,2-Bis(benzamido)acetate (25a)Fe Catalysis: Compound 25a was synthesized according to the GPfrom benzamide (242 mg, 2.0 mmol, 2.0 equiv), ethyl glyoxalate(0.10 mL, 1.0 mmol, 1.0 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol,5 mol%) in MeNO2 (2.0 mL). After stirring for 24 h at 80 °C, the whiteprecipitate was filtered, and dried under reduced pressure. The de-sired product was isolated as a white solid (325 mg, ~100%).Mp (decomp.); Rf = 0.26 (n-hexane/EtOAc = 7:3).1H NMR (400 MHz, CDCl3): δ = 8.00–7.70 (m, 6 H), 7.55–7.42 (m, 6 H),5.88 (t, J = 6.7 Hz, 1 H), 4.33 (dd, J = 14.1, 7.0 Hz, 2 H), 1.30 (t, J = 7.1Hz, 3 H).Analytical and spectral data are consistent with those reported in theliterature.37
Ethyl 2,2-Dimesitylacetate (26)Fe Catalysis: Compound 26 was synthesized according to the GP fromethyl glyoxalate (0.10 mL, 1.0 mmol, 1.0 equiv), mesitylene (0.42 mL,3.0 mmol, 3.0 equiv), and FeCl3·6H2O (13 mg, 0.025 mmol, 5 mol%) inMeNO2 (4.0 mL). The reaction mixture was stirred for 24 h at 80 °C.Purification by chromatography (n-hexane/EtOAc = 20:1 → 9:1) yield-ed the product as a colorless solid (320 mg, 99%).
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Mp 100–106 °C; Rf = 0.72 (n-hexane/EtOAc = 9:1).1H NMR (400 MHz, CDCl3): δ = 6.79 (s, 4 H), 4.24 (q, J = 7.1 Hz, 2 H),2.24 (s, 6 H), 2.07 (s, 12 H), 1.27 (t, J = 7.1 Hz, 3 H).Analytical and spectral data are consistent with those reported in theliterature.38
Ethyl 2-Hydroxy-2-mesitylacetate (27)Fe Catalysis: Compound 27 was synthesized according to the GP fromethyl glyoxalate (0.24 mL, 1.2 mmol, 1.0 equiv), mesitylene (0.42 mL,3.0 mmol, 3.0 equiv), 2,2′-bipyridine (5 mg, 0.03 mmol, 3 mol%), andFe(ClO4)3 (7 mg, 0.02 mmol, 2 mol%) in MeNO2 (2.0 mL). The reactionmixture was stirred for 24 h at 80 °C. Purification by chromatography(hexane/EtOAc = 4:1) yielded the product as a colorless oil (176 mg,66%).Rf = 0.51 (n-hexane/EtOAc = 7:3).1H NMR (400 MHz, CDCl3): δ = 6.84 (s, 2 H), 5.52 (d, J = 2.8 Hz, 1 H),4.34–4.11 (m, 2 H), 3.22 (d, J = 2.8 Hz, 1 H), 2.33 (s, 6 H), 2.26 (s, 3 H),1.22 (t, J = 7.1 Hz, 3 H).Analytical data are consistent with those reported in the literature.39
Acknowledgment
This work was financially supported by the Fonds der Chemischen In-dustrie (Liebig Fellowship to G.M. and A.E.S.), the Evonik Stiftung (Fel-lowship to J.H.), the Stiftung Polytechnische Gesellschaft Frankfurtam Main (Fellowship to T.B.), and the Goethe-University Frankfurt(Nachwuchs im Fokus-Program). We would like to thank Prof.Michael Göbel (Goethe-University Frankfurt) for his support as wellas Rockwood Lithium GmbH (Frankfurt) and Evonik Industries AG(Hanau) for the generous gift of chemicals.
Supporting Information
Supporting information for this article is available online athttp://dx.doi.org/10.1055/s-0035-1561499. Supporting InformationSupporting Information
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 849–879